Novel benzazepines and related heterocyclic derivatives which are useful as orexin receptor antagonists

ABSTRACT

The invention relates to novel benzazepines and related heterocyclic derivatives (I) and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as orexin receptor antagonists.

[0001] The present invention relates to novel benzazepines and relatedheterocyclic derivatives of the general formula (I) and their use aspharmaceuticals. The invention also concerns related aspects includingprocesses for the preparation of the compounds, pharmaceuticalcompositions containing one or more compounds of formula (I), andespecially their use as orexin receptor antagonists.

[0002] The orexins (hypocretins) comprise two neuropeptides produced inthe hypothalamus: the orexin A (OX-A) (a 33 aminoacid peptide) and theorexin B (OX-B) (a 28 aminoacid peptide). Orexins are found-to stimulatefood consumption in rats suggesting a physiological role for thesepeptides as mediators in the central feedback mechanism that regulatesfeeding behavior (Sakurai T. et al., Cell 1998, 92, 573-585). On theother hand, it was also proposed that orexins regulate states of sleepand wakefulness opening potentially novel therapeutic approaches fornarcoleptic patients (Chemelli R. M. et al., Cell 1999, 98, 437-451).Two orexin receptors have been cloned and characterized in mammals. Theybelong to the superfamily of G-protein coupled receptor (Sakurai T. etal., Cell 1998, 92, 573-585). The orexin-1 receptor (OX₁) is selectivefor OX-A and the orexin-2 receptor (OX₂) is capable to bind OX-A as wellas OX-B.

[0003] Orexin receptors are found in the mammalian host and may beresponsible for many biological functions such as pathologies including,but not limited to, depression; anxiety; addictions; obsessivecompulsive disorder; affective neurosis; depressive neurosis; anxietyneurosis; dysthymic disorder; behaviour disorder; mood disorder, sexualdysfunction; psychosexual dysfunction; sex disorder; schizophrenia;manic depression; delirium; dementia; severe mental retardation anddyskinesias such as Huntington's disease and Tourette syndrome; eatingdisorders such as anorexia, bulimia, cachexia and obesity; diabetes;appetite/taste disorders; vomiting/nausea; asthma; cancer; Parkinson'sdisease; Cushing's syndrome/disease; basophil adenoma; prolactinoma;hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma;hypothalamic diseases, inflammatory bowel disease; gastric diskinesia;gastric ulcus; Froehlich's syndrome; adrenohypophysis disease;hypophysis disease; pituitary growth hormone; adrenohypophysishypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism;Kallman's syndrome (anosmia, hyposmia); functional or psychogenicamenorrhea; hypopituitarism; hypothalamic hypothyroidism;hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia;hypothalamic disorders of growth hormone deficiency; idiopathic growthdeficiency; dwarfism; gigantism; acromegaly; disturbed biological andcircadian rhythms; sleep disturbances associated with diseases such asneurological disorders, neuropathic pain and restless leg syndrome;heart and lung diseases, acute and congestive heart failure;hypotension; hypertension; urinary retention; osteoporosis; anginapectoris; myocardinal infarction; ischaemic or haemorrhagic stroke;subarachnoid haemorrhage; ulcers; allergies; benign prostatichypertrophy; chronic renal failure; renal disease; impaired glucosetolerance; migraine; hyperalgesia; pain; enhanced or exaggeratedsensitivity to pain such as hyperalgesia, causalgia, and allodynia;acute pain; burn pain; atypical facial pain; neuropathic pain; backpain; complex regional pain syndrome I and II; arthritic pain; sportsinjury pain; pain related to infection e.g. HIV, post-chemotherapy pain;post-stroke pain; post-operative pain; neuralgia; conditions associatedwith visceral pain such as irritable bowel syndrome, migraine andangina; urinary bladder incontinence e.g. urge incontinence; toleranceto narcotics or withdrawal from narcotics; sleep disorders; sleep apnea;narcolepsy; insomnia; parasomnia; jet-lag syndrome; and neurodegerativedisorders including nosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration epilepsy; seizure disorders and otherdiseases related to orexin.

[0004] The present invention provides benzazepines and relatedheterocyclic derivatives which are non-peptide antagonists of humanorexin receptors, in particular OX₁ and OX₂ receptors. In particular,these compounds are of potential use in the treatment of obesity and/orsleep disorders.

[0005] So far not much is known about low molecular weight compoundswhich have a potential to antagonise either specifically OX₁ or OX₂ orboth receptors at the same time. Recently WO 99/09024, WO 99/58533, WO00/47577 and WO 00/47580 have been published wherein phenyl urea andphenyl thiourea derivatives are described as being preferably OX₁receptor antagonists. Also quite recently WO 00/47576 describedcinnamide derivatives as OX₁ receptor antagonists. The novel compoundsof the present invention belong to an entirely different class of lowmolecular weight compounds as compared to all prior art orexin receptorantagonists so far published.

[0006] The present invention relates to novel benzazepines and relatedheterocyclic derivatives of the general formula (I).

[0007] wherein:

[0008] R¹, R², R³, R⁴ independently represent cyano, nitro, halogen,hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, loweralkenyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyloxy, aryloxy,aralkyloxy, heterocyclyloxy, heterocyclylalkyloxy, R¹¹CO—, NR¹²R¹³CO—,R¹²R¹³N—, R¹¹OOC—, R¹¹SO₂NH—, or R¹⁴—CO—NH—, or R² and R³ together aswell as R¹ and R² together and R³ and R⁴ together may form with thephenyl ring a five, six or seven-membered saturated ring containing oneor two oxygen atoms;

[0009] R⁵ represents aryl, aralkyl, lower alkyl, lower alkenyl,trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl;

[0010] R⁶ represents hydrogen, aryl, aralkyl, lower alkyl, loweralkenyl, trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyl-loweralkyl;

[0011] R⁷, R⁸ independently represent hydrogen, aryl, aralkyl, loweralkyl, lower alkenyl, cycloalkyl, heterocyclyl or heterocyclyl-loweralkyl;

[0012] R⁹, R¹⁰ independently represent hydrogen, aryl, arylcycloalkyl,aralkyl, lower alkyl, lower alkenyl, lower alkinyl, cycloalkyl,heterocyclyl or heterocyclyl-lower alkyl, in which substituents one,several, or all hydrogen atoms may be replaced by halogen or in whichone or two hydrogen atoms may be replaced by hydroxy, nitro, cyano,trifluoromethyl, trifluoromethoxy, —O-lower alkyl, —NH-lower alkyl,—N(lower alkyl)₂, —S-lower alkyl, —COO-lower alkyl, —CONH-lower alkyl,—CON(lower alkyl)₂, —CO-lower alkyl, —NCO-lower alkyl, —O-lower alkenylwith 3 to 5 carbon atoms, —NH-lower alkenyl with 3 to 5 carbon atoms,—N(lower alkenyl with 3 to 5 carbon atoms)₂, —S-lower alkenyl with 3 to5 carbon atoms, —COO-lower alkenyl with 3 to 5 carbon atoms, —CONH-loweralkenyl with 3 to 5 carbon atoms, —CON(lower alkenyl with 3 to 5 carbonatoms)₂, —CO-lower alkenyl with 3 to 5 carbon atoms, —NHCO-lower alkenylwith 3 to 5 carbon atoms, —O-lower alkinyl with 3 to 5 carbon atoms,—NH-lower alkinyl with 3 to 5 carbon atoms, —N(lower alkinyl with 3 to 5carbon atoms)₂, —S-lower alkinyl with 3 to 5 carbon atoms, —COO-loweralkinyl with 3 to 5 carbon atoms, —CONH-lower alkinyl with 3 to 5 carbonatoms, —CON(lower alkinyl with 3 to 5 carbon atoms)₂, —CO-lower alkinylwith 3 to 5 carbon atoms, —NHCO-lower alkinyl with 3 to 5 carbon atoms;

[0013] R¹¹ represents lower alkyl, aryl, aralkyl, heterocyclyl orheterocyclyl-lower alkyl;

[0014] R¹²and R¹³ independently represent hydrogen, lower alkyl,cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl;

[0015] R¹⁴ represents lower alkyl, aryl, cycloalkyl, heterocyclyl,R¹²R¹³N—, R¹¹O—;

[0016] —X—Y— independently represents —CH₂—CH₂—, —O—CH₂—, —S—CH₂—,—SO₂—CH₂— and —NR¹⁵—CO—;

[0017] R¹⁵ represents hydrogen, lower alkyl or aralkyl;

[0018] and optically pure enantiomers, mixtures of enantiomers such as,for example, racemates, optically pure diastereoisomers, mixtures ofdiastereoisomers, diastereoisomeric racemates, mixtures ofdiastereoisomeric racemates, or meso forms and pharmaceuticallyacceptable salts thereof.

[0019] In the present description the term “lower alkyl”, alone or incombination, signifies a straight-chain or branched-chain alkyl groupwith 1 to 8 carbon atoms, preferably a straight or branched-chain alkylgroup with 1-4 carbon atoms. Examples of straight-chain and branchedC₁-C₈ alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl,n-pentyl, n-hexyl, n-heptyl, n-octyl, isobutyl, tert-butyl, the isomericpentyls, the isomeric hexyls, the isomeric heptyls and the isomericoctyls, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl,and tert-butyl.

[0020] The term “lower alkenyl”, alone or in combination, if nototherwise defined signifies a straight-chain or branched-chain alkenylgroup with 2 to 5 carbon atoms, preferably allyl and vinyl.

[0021] The term “lower alkinyl”, alone or in combination, signifies astraight-chain or branched-chain alkinyl group with 2 to 5 carbon atoms,preferably propargyl and n-butinyl.

[0022] The term “lower alkoxy”, alone or in combination, signifies agroup of the formula lower alkyl-O— in which the term “lower alkyl” hasthe previously given significance, such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, preferablymethoxy and ethoxy.

[0023] Lower alkenyloxy groups are preferably vinyloxy and allyloxy.

[0024] The term “cycloalkyl”, alone or in combination, signifies acycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkylring with 3 to 6 carbon atoms. Examples of C₃-C₈ cycloalkyl groups arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl, preferably cyclopropyl, cyclopentyl, cyclohexyl andparticularly cyclohexyl or lower alkyl substituted cycloalkyl which maypreferably be substituted with lower alkyl, such as methyl-cyclopropyl,dimethyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl,methyl-cyclohexyl, dimethyl-cyclohexyl.

[0025] The term “aryl”, alone or in combination, signifies a phenyl ornaphthyl group which optionally carries one or more substituents,preferably one or two substituents, each independently selected fromcyano, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, loweralkenyloxy, nitro, trifluoromethyl, trifluoromethoxy, amino, carboxy andthe like, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-tert-butoxyphenyl,4-fluorophenyl, 2-chlorophenyl, 4-hydroxyphenyl, 1-naphthyl and2-naphthyl. Preferred are carboxyphenyl, lower alkoxy-phenyl,hydroxyphenyl and particularly phenyl.

[0026] The term “aralkyl”, alone or in combination, signifies a loweralkyl or cycloalkyl group as previously defined in which one hydrogenatom has been replaced by an aryl group as previously defined. Preferredare benzyl and benzyl substituted in the phenyl ring with hydroxy, loweralkyl, lower alkoxy or halogen preferably chlorine. Particularlypreferred is benzyl.

[0027] The term “arylcycloalkyl”, alone or in combination, signifies anarylcycloalkyl group wherein the cycloalkyl moiety consists of 4 to 7carbon atoms e.g. indanyl, tetrahydronaphthyl, benzocycloheptyl andbenzocyclobutyl. The aromatic moiety may be substituted with one or moresubstituents, preferably one or two-substituents, each independentlyselected from cyano, halogen, hydroxy, lower alkyl, lower alkenyl, loweralkoxy, lower alkenyloxy, nitro, trifluoromethyl, trifluoromethoxy,amino and carboxy.

[0028] For the term “heterocyclyl” and “heterocyclyl-lower alkyl”, theheterocyclyl group is preferably a 5- to 10-membered monocyclic orbicyclic ring, which may be saturated, partially unsaturated or aromaticcontaining for example 1, 2 or 3 heteroatoms selected from oxygen,nitrogen and sulphur which may be the same or different. Example of suchheterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl,isoquinolyl, thienyl, thiazolyl, isothiazolyl, furyl, imidazolyl,pyrazolyl, pyrrolyl, indazolyl, indolyl, isoindolyl, isoxazolyl,oxazolyl, quinoxalinyl, phthalazinyl, cinnolinyl, dihydropyrrolyl,isobenzofuranyl, tetrahydrofuranyl, dihydropyranyl. The heterocyclylgroup may have up to 5, preferably 1, 2 or 3 optional substituents.Examples of suitable substituents include halogen, lower alkyl, amino,nitro, cyano, hydroxy, lower alkoxy, carboxy and loweralkyloxy-carbonyls.

[0029] The term “halogen” signifies fluorine, chlorine, bromine oriodine and preferably fluorine and chlorine.

[0030] The term “carboxy”, alone or in combination, signifies a —COOHgroup.

[0031] A group of preferred compounds according to the present inventionare compounds of formula (II)

[0032] wherein:

[0033] R¹, R², R³, R⁴ independently represent cyano, nitro, halogen,hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, loweralkenyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyloxy, aryloxy,aralkyloxy, heterocyclyloxy, heterocyclylalkyloxy, R¹¹CO—, NR¹²R¹³CO—,R¹²R¹³N—, R¹¹OOC—, R¹¹SO₂NH—, or R¹⁴—CO—NH—, or R² and R³ together aswell as R¹ and R² together and R³ and R⁴ together may form with thephenyl ring a five, six or seven-membered saturated ring containing oneor two oxygen atoms;

[0034] R⁵ represents aryl, aralkyl, lower alkyl, lower alkenyl,trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl;

[0035] R⁶ represents hydrogen, aryl, aralkyl, lower alkyl, loweralkenyl, trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyl-loweralkyl;

[0036] R⁷, R⁸, R⁹, R¹⁰ independently represent hydrogen, aryl, aralkyl,lower alkyl, lower alkenyl, cycloalkyl, heterocyclyl orheterocyclyl-lower alkyl;

[0037] R¹¹ represents lower alkyl, aryl, aralkyl, heterocyclyl orheterocyclyl-lower alkyl;

[0038] R¹²and R¹³ independently represent hydrogen, lower alkyl,cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl;

[0039] R¹⁴ represents lower alkyl, aryl, cycloalkyl, heterocyclyl,R¹²R¹³N—, R¹¹O—;

[0040] —X—Y— independently represents —CH₂—CH₂—, —O—CH₂—, —S—CH₂—,—SO₂—CH₂— and —NR¹⁵—CO—;

[0041] R¹⁵ represents hydrogen, lower alkyl or aralkyl;

[0042] and optically pure enantiomers, mixtures of enantiomers such as,for example, racemates, optically pure diastereoisomers, mixtures ofdiastereoisomers, diastereoisomeric racemates, mixtures ofdiastereoisomeric racemates, or meso forms and pharmaceuticallyacceptable salts thereof.

[0043] Another group of preferred compounds according to the presentinvention are compounds of formula (III)

[0044] wherein:

[0045] R′¹ and R′² independently represent hydrogen, hydroxy, loweralkoxy, lower alkenyloxy or halogen or may form with the phenyl ring afive, six or seven membered-ring containing one or two oxygen atoms;

[0046] R′³ represents aryl, aralkyl, lower alkyl, lower alkenyl,cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl;

[0047] R′⁴, R′⁵ independently represent hydrogen, aryl, aralkyl, loweralkyl, lower alkenyl, cycloalkyl, heterocyclyl or heterocyclyl-loweralkyl;

[0048] —X—Y— independently represents —CH₂—CH₂—, —O—CH₂—, —S—CH₂—,—SO₂—CH₂— and —NR′⁶—CO—;

[0049] R′⁶ represents hydrogen, lower alkyl or aralkyl;

[0050] and optically pure enantiomers, mixtures of enantiomers such as,for example, racemates, optically pure diastereoisomers, mixtures ofdiastereoisomers, diastereoisomeric racemates, mixture ofdiastereoisomeric racemates, or meso forms and pharmaceuticallyacceptable salts thereof.

[0051] Examples of preferred compounds are:

[0052]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-naphthalen-1-ylmethyl-acetamide

[0053]N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-acetamide

[0054]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-2-yl-acetamide

[0055]2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-N-indan-2-yl-acetamide

[0056]2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-N-indan-1-yl-acetamide

[0057]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide

[0058]2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9-tetrahydro-5λ-thia-8-aza-benzocyclohepten-8-yl]-N-indan-2-yl-acetamide

[0059]2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9-tetrahydro-5λ-thia-8-aza-benzocyclohepten-8-yl]-N-indan-1-yl-acetamide

[0060]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide

[0061]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-2-yl-2-phenyl-acetamide

[0062]2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza-benzocyclohepten-8-yl]-N-naphthalen-1-ylmethyl-acetamide

[0063]2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza-benzocyclohepten-8-yl]-N-(2-ethoxy-benzyl)-acetamide

[0064]2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza-benzocyclohepten-8-yl]-N-indan-1-yl-acetamide

[0065]2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide

[0066]N-Benzyl-2-[9-(3,4-dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza-benzocyclohepten-8-yl]-acetamide

[0067]2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4yl]-N-indan-1-yl-acetamide

[0068]N-Butyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0069]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-2-phenyl-acetamide

[0070]N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0071]N-Cyclopentyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0072]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-furan-2-ylmethyl-2-phenyl-acetamide

[0073]{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-aceticacid ethyl ester

[0074]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-pyridin-4-ylmethyl-acetamide

[0075]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-pyridin-3-ylmethyl-acetamide

[0076]N-Cyclopropyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0077]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-oxo-tetrahydro-furan-3-yl)-2-phenyl-acetamide

[0078]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(4-methoxy-indan-1-yl)-acetamide

[0079]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-phenyl-indan-1-yl)-acetamide

[0080]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(4-methyl-indan-1-yl)-acetamide

[0081]2-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-3-hydroxy-propionicacid methyl ester

[0082]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-ethylcarbamoylmethyl-2-phenyl-acetamide

[0083]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-[(ethyl-methyl-carbamoyl)-methyl]-2-phenyl-acetamide

[0084]2-[1-(3,4-Dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide

[0085]2-[8-Benzyloxy-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide

[0086]3-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-propionicacid methyl ester

[0087]N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0088]N-(1H-Benzoimidazol-2-ylmethyl)-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0089]3-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-N,N-dimethyl-propionamide

[0090]3-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-N-ethyl-N-methyl-propionamide

[0091]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-methyl-1H-indol-3-ylmethyl)-2-phenyl-acetamide

[0092]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-isoxazol-5-ylmethyl-2-phenyl-acetamide

[0093]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1H-indol-3-ylmethyl)-2-phenyl-acetamide

[0094]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-methyl-1H-benzoimidazol-2-ylmethyl)-2-phenyl-acetamide

[0095]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-isoquinolin-1-ylmethyl-2-phenyl-acetamide

[0096]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-(4-[1,2,3]thiadiazol-4-yl-benzyl)-acetamide

[0097]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-methyl-1H-indazol-3-ylmethyl)-2-phenyl-acetamide

[0098]N-Cyanomethyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0099]N-(2-Acetylamino-ethyl)-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0100]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-(2,2,2-trifluoro-ethyl)-acetamide

[0101]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-methylsulfanyl-ethyl)-2-phenyl-acetamide

[0102]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-quinolin-2-ylmethyl-acetamide

[0103]N-(2-Cyano-ethyl)-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0104]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-methoxy-propyl)-2-phenyl-acetamide

[0105]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-ethoxy-propyl)-2-phenyl-acetamide

[0106]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0107]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-pyrazin-2-ylmethyl-acetamide

[0108]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-prop-2-ynyl-acetamide

[0109]N-tert-Butyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0110]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-methyl-butyl)-2-phenyl-acetamide

[0111]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3,3-dimethyl-butyl)-2-phenyl-acetamide

[0112]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-ethyl-propyl)-2-phenyl-acetamide

[0113]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-ethylsulfanyl-ethyl)-2-phenyl-acetamide

[0114]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-hydroxy-ethyl)-2-phenyl-acetamide

[0115]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-hydroxy-propyl)-2-phenyl-acetamide

[0116][1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid N′,N′-dimethyl-hydrazide

[0117]2-[8-Allyloxy-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide

[0118]2-[1-(3,4-Dimethoxy-benzyl)-7-methoxy-8-propoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide

[0119]2-[1-(3,4-Dimethoxy-benzyl)-8-isopropoxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide

[0120]2-[8-(2,2-Difluoro-ethoxy)-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide

[0121]N-Benzo[1,3]dioxol-5-ylmethyl-2-[8-(2,2-difluoro-ethoxy)-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0122]N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-8-isopropoxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0123]2-[5-(3,4-Dichloro-benzyl)-7,8-dimethoxy-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-N-indan-1-yl-acetamide

[0124]2-[1-(S)-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide

[0125]2-[1-(S)-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-2-yl-acetamide

[0126] Examples of particularly preferred compounds are:

[0127]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-2-yl-acetamide

[0128]2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-N-indan-1-yl-acetamide

[0129]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide

[0130]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide

[0131]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-2-yl-2-phenyl-acetamide

[0132]N-Butyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0133]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-2-phenyl-acetamide

[0134]N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0135]N-Cyclopentyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0136]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-furan-2-ylmethyl-2-phenyl-acetamide

[0137]{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-aceticacid ethyl ester

[0138]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-pyridin-3-ylmethyl-acetamide

[0139]3-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-propionicacid methyl ester

[0140]N-(1H-Benzoimidazol-2-ylmethyl)-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0141]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-methyl-1H-indol-3-ylmethyl)-2-phenyl-acetamide

[0142]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-isoxazol-5-ylmethyl-2-phenyl-acetamide

[0143]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1H-indol-3-ylmethyl)-2-phenyl-acetamide

[0144]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-isoquinolin-1-ylmethyl-2-phenyl-acetamide

[0145]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-(4-[1,2,3]thiadiazol-4-yl-benzyl)-acetamide

[0146]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-methyl-1H-indazol-3-ylmethyl)-2-phenyl-acetamide

[0147]N-Cyanomethyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0148]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-(2,2,2-trifluoro-ethyl)-acetamide

[0149]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-methylsulfanyl-ethyl)-2-phenyl-acetamide

[0150]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-quinolin-2-ylmethyl-acetamide

[0151]N-(2-Cyano-ethyl)-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0152]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-methoxy-propyl)-2-phenyl-acetamide

[0153]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-ethoxy-propyl)-2-phenyl-acetamide

[0154]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-pyrazin-2-ylmethyl-acetamide

[0155]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-prop-2-ynyl-acetamide

[0156]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-methyl-butyl)-2-phenyl-acetamide

[0157]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3,3-dimethyl-butyl)-2-phenyl-acetamide

[0158]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-ethyl-propyl)-2-phenyl-acetamide

[0159]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-ethylsulfanyl-ethyl)-2-phenyl-acetamide

[0160]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-hydroxy-ethyl)-2-phenyl-acetamide

[0161]2-[8-Allyloxy-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide

[0162]2-[1-(3,4-Dimethoxy-benzyl)-7-methoxy-8-propoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide

[0163]2-[1-(3,4-Dimethoxy-benzyl)-8-isopropoxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide

[0164]2-[8-(2,2-Difluoro-ethoxy)-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide

[0165]N-Benzo[1,3]dioxol-5-ylmethyl-2-[8-(2,2-difluoro-ethoxy)-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0166]N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-8-isopropoxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide

[0167]2-[1-(S)-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide

[0168]2-[1-(S)-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-2-yl-acetamide

[0169] Examples of physiologically usable or pharmaceutically acceptablesalts of the compounds of general formula (I) are salts withphysiologically compatible mineral acids such as hydrochloric acid,sulfuric or phosphoric acid, or with organic acids such asmethanesulphonic acid, acetic acid, trifluoroacetic acid, citric acid,fumaric acid, maleic acid, tartaric acid, succinic acid or salicylicacid. Compounds of formula (I) with acidic groups can also form saltswith physiologically compatible bases. Examples of such salts are alkalimetal, earth alkali metal, ammonium and alkylammonium salts such as Na,K, Ca or tetraalkylammonium salts. The compounds of general formula (I)can also be present in the form of a zwitterion.

[0170] Preferred compounds as described above have IC₅₀ values below1000 nM; particularly preferred compounds have IC₅₀ values below 100 nMwhich have been determinated with the FLIPR (Fluorometric Imaging PlatesReader) method described in the beginning of the experimental section.

[0171] The compounds of the general formula (I) and theirpharmaceutically usable salts can be used for the treatment of diseasesor disorders where an antagonist of a human orexin receptor is requiredsuch as obesity, diabetes, cardiovascular disorders, cancer,prolactinoma, pain, narcolepsy, insomnia, sleep apnea, parasomnia,depression, anxiety, addictions, schizophrenia, neurodegenerativedisorders and dementia.

[0172] The compounds of general formula (I) and their pharmaceuticallyusable salts are particularly useful for the treatment of obesity andsleep disorders.

[0173] The compounds of general formula (I) and their pharmaceuticallyusable salts can be used as medicament (e.g. in the form ofpharmaceutical preparations). The pharmaceutical preparations can beadministered in enteral or oral form (e.g. in the form of tablets,coated tablets, dragees, hard and soft gelatine capsules, solutions,emulsions or suspensions), nasally (e.g. in the form of nasal sprays) orrectally (e.g. in the form of suppositories). However, theadministration can also be effected parenterally, such asintramuscularly or intravenously (e.g. in the form of injectionsolutions).

[0174] The compounds of general formula (I) and their pharmaceuticallyusable salts can be processed with pharmaceutically inert, inorganic ororganic excipients for the production of tablets, coated tablets,dragees, and hard gelatine capsules. Lactose, corn starch or derivativesthereof, talc, stearic acid or its salts etc. can be used, for example,as such adjuvants for tablets, dragees, and hard gelatine capsules.

[0175] Suitable adjuvants for soft gelatine capsules, are, for example,vegetable oils, waxes, fats, semi-solid substances and liquid polyols,etc.

[0176] Suitable adjuvants for the production of solutions and syrupsare, for example, water, polyols, saccharose, invert sugar, glucose,etc.

[0177] Suitable adjuvants for injection solutions are, for example,water, alcohols, polyols, glycerol, vegetable oils, etc.

[0178] Suitable adjuvants for suppositories are, for example, natural orhardened oils, waxes, fats, semi-solid or liquid polyols, etc.

[0179] Moreover, the pharmaceutical preparations can containpreservatives, solubilizers, viscosity-increasing substances,stabilizers, wetting agents, emulsifiers, sweeteners, colorants,flavorants, salts for varying the osmotic pressure, buffers, maskingagents or antioxidants. They can also contain still othertherapeutically valuable substances. The invention also relates toprocesses for the preparation of compounds of general formula (I).

[0180] The compounds of general formula (I) of the present invention areprepared according to the general sequence of reactions outlined in theschemes below, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R¹⁵ are as defined in general formula (I) above. As thecase may be any compound obtained with one or more optically activecarbon atom may be resolved into pure enantiomers or diastereomers,mixtures of enantiomers or diastereomers, diastereomeric racemates andthe meso-forms in a manner known per se.

[0181] The compounds obtained may also be converted into apharmaceutically acceptable salt thereof in a manner known per se.

[0182] The compounds of the general formula (I) may be prepared bystandard procedures

[0183] (Procedure A wherein R⁷ and R⁸ are hydrogen atoms and Procedure Bwherein R⁷ and/or R⁸ are other than hydrogen) shown in Scheme 1 usingsynthesized benzazepine and related heterocyclic derivatives.

[0184] Benzazepine derivatives wherein X and Y are CH₂ and R⁶ ishydrogen might be prepared from the corresponding phenylpropylamine bycoupling with the desired carboxylic acid or acyl chloride followed bytreatment with POCl₃ and finally NaBH₄ (Bischler-Napieralski reaction)as shown in Scheme 2a (S. Kano et al., Chem. Pharm. Bull. 1977, 25, 10,2510-2515).

[0185] Benzazepines with variable substituents on position 8 might beprepared by hydrogenolysis of the corresponding8-benzyloxy-1,3,4,5-tetrahydro-benzazepines followed by O-alkylationwith the appropriate electrophile (Scheme 2b, —OR′₁₁ being included inthe definition of R₃). The benzylethers can be obtained with theprevious procedure (Scheme 2a) applied to3-(4-benzyloxy-phenyl)-propionic acid derivatives.

[0186] Benzothiazepine and benzoxazepine derivatives wherein X is O orS, Y is CH₂ and R⁶ is hydrogen might be prepared from the correspondingarylamine by coupling with the desired carboxylic acid or acyl chloridefollowed by treatment with POCl₃ and finally NaBH₄ (Bischler-Napieralskireaction) as shown in Scheme 3.

[0187] 1,3,4,5-Tetrahydro-2H-1,4-benzodiazepin-2-one derivatives whereinX is NR¹⁵, Y is CO and R⁶ is hydrogen might be prepared byFriedel-Crafts acylation of the appropriate acetylated-aniline with therespective acyl chloride (Sternbach L. H. et al., J. Org. Chem. 1962,27, 3781-3788), followed by N-deprotection-cyclisation by treatment withmethyl esters of α-amino acids (Sternbach L. H. et al., J. Org. Chem.1962, 27, 3788-3796) and finally hydrogenolysis of the dihydro compound(Fryer R. I. et al., J. Med. Chem. 1964, 386-389) (Scheme 4a). Analternative synthetic approach to such1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivatives is describedin Scheme 4b. According to this methodology, the arylketone derivativeis obtained by Friedel-Crafts acylation and a subsequent nitration andhydrogenation led to the aniline derivative. The1,3-dihydro-benzo[e][1,4]diazepin-2-one skeleton is then obtainedaccording to a well-described cyclisation procedure involvingbromoacetyl bromide and ammonia (Bock M. G. et al., J. Org. Chem. 1987,3232-3239; Zhang W. et al., J. Med. Chem. 1994, 745-757). At this stagethe amide can be N-alkylated and the1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivative was finallyobtained by hydride reduction (Gilman N. W. et al., J. Am. Chem. Soc.1990, 3969-3978).

[0188] For the preparation of benzazepine derivatives withelectron-withdrawing substituents on the phenyl ring, the previousprocedures based on the Bischler-Napieralski reaction are incompatible.Therefore cyano groups might be introduced by reaction of a triflatewith cyanide ions in the presence of palladium(0) (Austin N. E. et al.,Bioorg. Med. Chem. Lett. 2000, 10, 2553-2555; Ritter K. et al.,Synthesis 1993, 735; Selnick H. G. et al., Synth. Commun. 1995, 25, 20,3255-3262) (Scheme 5).

[0189] Carboxylate groups might also be introduced by reaction of atriflate with carbon monoxide and an alcohol in the presence ofpalladium(0) (Roth G. P. et al., Tetrahedron Lett. 1992, 33, 1959; Ma D.et al., Bioorg. Med. Chem. Lett. 1998, 8, 18, 2447-2450; Fisher M. J. etal., J. Med. Chem. 1997, 40, 2085-2101; Kraus G. A. et al., TetrahedronLett. 1994, 35, 9189-9190). These carboxylate functions can subsequentlybe converted into amino functionalties by hydrolysis followed by Curtiusreaction (Scheme 6).

[0190] Halogen containing 2-benzazepines may be prepared by treatment ofhalogenated tetralone oximes with POCl₃/DMF and the resulting1,3,4,5-tetrahydro-1-oxo-2H-2-benzazepine-2-carboxaldehydes can besubsequently deformylated and reduced (Majo V. J. et al., Synth. Commun.1995, 25, 23, 3863-3868) (Scheme 7).

[0191] 8-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine might be prepared byregioselective nitration of 2,3,4,5-tetrahydro-1H-2-benzazepin-1-oneusing potassium nitrate and sulfuric acid (Grunewald G. L. et al., J.Heterocyclic Chem. 1994, 31, 1609-1617) (Scheme 8).

[0192] The preparation of enantiomerically pure1-substituted-2-tetrahydrobenzazepine derivatives (Scheme 9) was basedon a methodology described for the synthesis of optically pure1-substituted tetrahydroisoquinolines (Polniaszek R. P. et al., J. Am.Chem. Soc. 1989, 111, 4859-4863). The key step of this asymmetricsynthesis is a stereoselective hydride reduction of a chiral imminiumion obtained by Bischler-Napieralski reaction. The chirality resident inthe substrate would be derived from the commercially available(S)-(−)-α-phenethylamine.

EXPERIMENTAL SECTION Abbreviations

[0193] AcOEt Ethyl acetate

[0194] Bn Benzyl

[0195] Boc Tert-butoxycarbonyl

[0196] BSA Bovine serum albumine

[0197] CHO Chinese hamster ovary

[0198] DMF Dimethylformamide

[0199] DMSO Dimethylsulfoxide

[0200] ES Electron spray

[0201] FCS Foetal calf serum

[0202] FLIPR Fluorescent imaging plate reader

[0203] HBSS Hank's balanced salt solution

[0204] HEPES 4-(2-Hydroxyethyl)-piperazine-1-ethanesulfonic acid

[0205] HV High vacuum

[0206] MeOH Methanol

[0207] Min minute(s)

[0208] MS Mass spectroscopy

[0209] LC Liquid chromatography

[0210] PyBOPBenzotriazole-1-yl-oxy-tris-pyrrolidino-Phosphoniumhexafluorophosphate

[0211] R_(f) Retention front

[0212] rt retention time

[0213] RT Room temperature

[0214] TEA Triethylamine

[0215] TFA Trifluoroacetic acid

[0216] Tf CF₃SO₂—

[0217] THF Tetrahydrofuran

[0218] TLC Thin layer chromatography

[0219] I. Biology

[0220] Determination of OX₁ and OX₂ Receptor Antagonist Activities

[0221] The OX₁ and OX₂ receptor antagonist activities of the compoundsof general formula (I) were determined in accordance with the followingexperimental method.

[0222] Experimental Method:

[0223] Intracellular Calcium Measurements

[0224] Chinese hamster ovary (CHO) cells expressing the human orexin-1receptor and the human orexin-2 receptor, respectively, were grown inculture medium (Ham F-12 with L Glutamine) containing 300 μg/ml G418,100 U/ml penicillin, 100 μg/ml streptomycin and 10% inactivated foetalcalf serum (FCS).

[0225] The cells were seeded at 80'000 cells/well into 96-well blackclear bottom sterile plates (Costar) which had been precoated with 1%gelatine in Hanks' Balanced Salt Solution (HBSS). All reagents were fromGibco BRL.

[0226] The seeded plates were incubated overnight at 37° C. in 5% CO₂.

[0227] Human orexin-A as an agonist was prepared as 1 mM stock solutionin methanol:water (1:1), diluted in HBSS containing 0.1% BSA and 2 mMHEPES for use in the assay at a final concentration of 10 nM.

[0228] Antagonists were prepared as 10 mM stock solution in DMSO, thendiluted in 96-well plates, first in DMSO, then in HBSS containing 0.1%bovine serum albumin (BSA) and 2 mM HEPES.

[0229] On the day of the assay, 100 μl of loading medium (HBSScontaining 1% FCS, 2 mM HEPES, 5 mM probenecid (Sigma) and 3 μM of thefluorescent calcium indicator fluo-3 AM (1 mM stock solution in DMSOwith 10% pluronic acid Molecular Probes)) was added to each well.

[0230] The 96-well plates were incubated for 60 min at 37° C. in 5% CO₂.The loading solution was then aspirated and cells were washed 3 timeswith 200 μl HBSS containing 2.5 mM probenecid, 0.1% BSA, 2 mM HEPES. 100μl of that same buffer was left in each well.

[0231] Within the Fluorescent Imaging Plate Reader (FLIPR, MolecularDevices), antagonists were added to the plate in a volume of 50 μl,incubated for 20 min and finally 100 μl of agonist was added.Fluorescence was measured for each well at 1 second intervals, and theheight of each fluorescence peak was compared to the height of thefluorescence peak induced by 10 nM orexin-A with buffer in place ofantagonist. For each antagonist; IC₅₀ values (the concentration ofcompound needed to inhibit 50% of the agonistic response) weredetermined. Selected compounds are displayed in Table 1. TABLE 1 IC₅₀(nM) OX₁ OX₂ Example 3 99 >10000 Example 5 64 7900 Example 9 23 1239Example 20 23 231 Example 23 21 189 Example 25 41 241 Example 34 41 9192Example 35 32 7041 Example 68 12 174 Example 69 9 349

[0232] II. Chemistry

[0233] The following examples illustrate the preparation ofpharmacologically active compounds of the invention but do not at alllimit the scope thereof. All temperatures are stated in ° C. Allhydrochloride salts were prepared by dissolving the free base indichloromethane and treating the resulting solution with an excess ofHCl in 2-propanol (5-6M).

[0234] A. Starting Materials: Synthesis of Tetrahydrobenzazepine andRelated Heterocyclic Derivatives:

[0235] 3-(3,4-Dimethoxy-phenyl)-propionamide

[0236] To a stirred solution of 3-(3,4-dimethoxy-phenyl)-propionic acid(10.0 g, 47.56 mmol) in dry THF (175 ml), under nitrogen, was added TEA(7.3 ml, 52.44 mmol), and the resulting mixture was cooled to −10° C.before ethyl chloroformate (5 ml, 52.47 mmol) was added dropwise. Afterstirring at −10° C. (20 min), ammonium hydroxide (25% in water, 105 ml)in THF (105 ml) was added and the mixture was stirred at −15° C. for 30min and then at RT for 1.5 h. The reaction mixture was concentrated invacuo, extracted three times with CH₂Cl₂ and the combined organicextracts were washed with saturated aqueous NaHCO₃ and brine. Theorganic phase was dried over anhydrous MgSO₄, filtered and concentratedto give the title compound (9.73 g, 46.50 mmol, 97%) as a colorlesssolid. No further purification of the crude amide was necessary.

[0237] LC-MS: rt=2.94 min, 210 (M+1, ES+).

[0238] 3-(3,4-Dimethoxy-phenyl)-propylamine

[0239] A solution of 3-(3,4-dimethoxy-phenyl)--propionamide (11.09 g,53.00 mmol) in anhydrous THF (400 ml) was slowly added to a stirred,ice-cooled suspension of LiAlH₄ (4.02 g, 106.00 mmol) in anhydrous THF(170 ml). Upon completion of the addition, the mixture was stirred atreflux for 2 h. After cooling to 0° C., H₂O (5 ml) and NaOH 1N (5 ml)were added dropwise to decompose the excess of hydride. The suspensionwas then filtered and the residue after evaporation was partitionedbetween H₂O (40 ml) and CH₂Cl₂ (100 ml). The organic layer was washedwith saturated aqueous NaHCO₃ and brine, dried over anhydrous MgSO₄, andconcentrated under reduced pressure to give the crude amine (7.00 g,35.84 mmol, 68%) as a yellow oil.

[0240]¹H-NMR (300 MHz, CDCl₃) δ: 6.9-6.6 (3H, m), 3.9-3.8 (6H, d),2.9-2.7 (2H, m), 2.65-2.55 (2H, m), 1.9-1.75 (2H, m).

[0241]2-(3,4-Dimethoxy-phenyl)-N-[3-(3,4-dimethoxy-phenyl)-propyl]-acetamide

[0242] A solution of 3-(3,4-dimethoxy-phenyl)-propylamine (12.51 g,64.06 mmol) and TEA (10 ml, 71.84 mmol) in anhydrous THF (70 ml) wascooled to 0° C. and (3,4-dimethoxy-phenyl)-acetyl chloride (13.75 g,64.07 mmol) in THF (28 ml) was added dropwise. After stirring at RT for13 h under nitrogen, a saturated aqueous NaHCO₃ solution was added andthe reaction mixture was extracted three times with AcOEt. The organicphase was dried over anhydrous MgSO₄, filtered and the solvent wasremoved in vacuo. A subsequent washing of the crude solid with toluenegave the title compound (12.81 g, 34.30 mmol, 53%) as a beige solid.

[0243] LC-MS: rt=4.00 min, 374 (M+1, ES+).

[0244]1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine

[0245] A mixture of2-(3,4-dimethoxy-phenyl)-N-[3-(3,4-dimethoxy-phenyl)-propyl]-acetamide(6.16 g, 16.49 mmol) and POCl₃ (4.95 ml, 54.07 mmol) in anhydrousacetonitrile (185 ml) was stirred at reflux for 4 h under nitrogen.After cooling, the reaction mixture was concentrated in vacuo and theresidue was dissolved in MeOH (125 ml). The solution was cooled to 0° C.and NaBH₄ (4.31 g, 113.93 mmol) was added portionwise. After stirring at0° C. for 2 h under nitrogen, the reaction mixture was poured into H₂Oand extracted three times with CH₂Cl₂. The combined organic extractswere washed with brine, dried over anhydrous MgSO₄, filtered andconcentrated to give a crude oil. Flash chromatography (CH₂Cl₂/MeOH:9/1) gave the title compound as a racemic mixture (2.29 g, 6.40 mmol,39%, yellow oil).

[0246] LC-MS: rt=3.02 min, 358 (M+1, ES+).

[0247][1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid methyl ester

[0248] A mixture of1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine(1.10 g, 3.08 mmol), TEA (1.3 ml, 9.33 mmol), and methylα-bromophenylacetate (487 μl, 3.09 mmol) in anhydrous toluene (13 ml)was stirred at reflux for 17 h under nitrogen. After cooling, thereaction mixture was dissolved in CH₂Cl₂ (40 ml), washed with H₂O (15ml), and the aqueous phase was extracted twice with CH₂Cl₂. The combinedorganic phases were dried over anhydrous MgSO₄, filtered andconcentrated to give a crude oil. Flash chromatography (AcOEt/hexane:1/1) gave the title compound as a mixture of stereoisomers (1.34 g, 2.65mmol, 86%, yellow oil).

[0249] LC-MS: rt=3.99 min. and rt=4.24 min (diastereoisomers), 506 (M+1,ES+).

[0250][1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid

[0251] To a solution of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid methyl ester (1.17 g, 2.31 mmol), in MeOH (9 ml) and dioxane (12ml), was added dropwise aqueous NaOH 2N (11 ml, 22 mmol). The resultingyellow homogeneous mixture was then stirred at 45° C. for 8 h. Thereaction mixture was then concentrated in vacuo and washed with Et₂O (5ml). The aqueous phase was acidified (pH=1) with HCl 2N and extractedthree times with CH₂Cl₂. The combined organic phases were dried overanhydrous MgSO₄, filtered and concentrated to give the titled carboxylicacid (1.14 g, 2.31 mmol, 100%) as a beige solid (mixture ofdiastereoisomers).

[0252] LC-MS: rt=3.58 min, 492 (M+1, ES+).

[0253] 3-(4-Benzyloxy-3-methoxy-phenyl)-propionic acid benzyl ester

[0254] A mixture of 3-(4-hydroxy-3-methoxy-phenyl)-propionic acid (5.1g, 25.99 mmol), anhydrous K₂CO₃ (25 g, 180.88 mmol) and benzyl bromide(7.5 ml, 63.14 mmol) in anhydrous acetone (100 ml) was stirred at refluxfor 7.5 h under nitrogen. After cooling, the reaction mixture wasfiltered and concentrated in vacuo. Flash chromatography (CH₂Cl₂) gavethe title compound (8.83 g, 23.45 mmol, 90%).

[0255] LC-MS: rt=5.65 min, 377 (M+1, ES+).

[0256] 3-(4-Benzyloxy-3-methoxy-phenyl)-propionic acid

[0257] To a solution of-3-(4-benzyloxy-3-methoxy-phenyl)-propionic acidbenzyl ester (11.03 g, 29.30 mmol), in MeOH (110 ml) and dioxane (145ml), was added dropwise aqueous NaOH 2N (139 ml, 278 mmol). Theresulting yellow homogeneous mixture was then stirred at 50° C. for 17h. The reaction mixture was then concentrated in vacuo and washed withEt₂O (100 ml). The aqueous phase was acidified (pH=1) with HCl 2N andextracted three times with CH₂Cl₂. The combined organic phases weredried over anhydrous MgSO₄, filtered and concentrated to give the titlecarboxylic acid (8.4 g, 29.30 mmol, 100%) as a colorless solid.

[0258] LC-MS: rt=4.53 min, 285 (M−1, ES−).

[0259] 3-(4-Benzyloxy-3-methoxy-phenyl)-propionamide

[0260] To a stirred solution of3-(4-benzyloxy-3-methoxy-phenyl)-propionic acid (8.38 g, 29.30 mmol) indry THF (110 ml), under nitrogen, was added TEA (4.5 ml, 32.33 mmol),and the resulting mixture was cooled to −10° C. before ethylchloroformate (3.1 ml, 32.53 mmol) was added dropwise. After stirring at−10° C. (20 min), ammonium hydroxide (25% in water, 65 ml) in THF (65ml) was added and the mixture was stirred at −15° C. for 30 min and thenat RT for 1.5 h. The reaction mixture was concentrated in vacuo,extracted three times with CH₂Cl₂ and the combined organic extracts werewashed with saturated aqueous NaHCO₃ and brine. The organic phase wasdried over anhydrous MgSO₄, filtered and concentrated to give the titlecompound (8.40 g, 29.30 mmol, 100%) as a colorless solid. No furtherpurification of the crude amide was necessary.

[0261] LC-MS: rt=4.08 min, 286 (M+1, ES+).

[0262] 3-(4-Benzyloxy-3-methoxy-phenyl)-propylamine

[0263] A solution of 3-(4-benzyloxy-3-methoxy-phenyl)-propionamide (7.85g, 27.53 mmol) in anhydrous THF (210 ml) was slowly added to a stirred,ice-cooled suspension of LiAlH₄ (2.09 g, 55.07 mmol) in anhydrous THF(90 ml). Upon completion of the addition, the mixture was stirred atreflux for 1 h. After cooling to 0° C., H₂O (15 ml) was added dropwiseto decompose the excess of hydride, and the resulting suspension wasthen filtered. The residue after evaporation was partitioned between H₂O(50 ml) and CH₂Cl₂ (100 ml). The organic layer was washed with NaHCO₃and brine, dried over anhydrous MgSO₄, and concentrated under reducedpressure to give the crude. amine (6.03 g, 22.22 mmol, 81%) as a yellowoil.

[0264] LC-MS: rt=3.20 min, 272 (M+1, ES+).

[0265]N-[3-(4-Benzyloxy-3-methoxy-phenyl)-propyl]-2-(3,4-dimethoxy-phenyl)-acetamide

[0266] A solution of 3-(4-benzyloxy-3-methoxy-phenyl)-propylamine (6.06g, 22.36 mmol) and TEA (3.5 ml, 25.14 mmol) in anhydrous THF (25 ml) wascooled to 0° C. and (3,4-dimethoxy-phenyl)-acetyl chloride (4.80 g,22.36 mmol) in THF (10 ml) was added dropwise. After stirring at RT for28 h under nitrogen, a saturated aqueous NaHCO₃ solution was added andthe reaction mixture was extracted three times with AcOEt. The organicphase was dried over anhydrous MgSO₄, filtered and the solvent wasremoved in vacuo. A subsequent washing of the crude solid with toluenegave the title compound (6.57 g, 14.61 mmol, 65%) as a beige solid.

[0267] LC-MS: rt=4.90 min, 450 (M+1, ES+).

[0268]8-Benzyloxy-1-(3,4-dimethoxy-benzyl)-7-methoxy-2,3,4,5-tetrahydro-1Hbenzo[c]azepine

[0269] A mixture ofN-[3-(4-benzyloxy-3-methoxy-phenyl)-propyl]-2-(3,4-dimethoxy-phenyl)-acetamide(6.04 g, 13.43 mmol) and POCl₃ (4.1 ml, 44.78 mmol) in anhydrousacetonitrile (350 ml) was stirred at reflux for 5 h under nitrogen.After cooling, the reaction mixture was concentrated in vacuo and theresidue was dissolved in MeOH (120 ml). The solution was cooled to 0° C.and NaBH₄ (3.50 g, 92.70 mmol) was added portionwise. After stirring at0° C. for 2 h under nitrogen, the reaction mixture was poured into H₂Oand extracted three times with CH₂Cl₂. The combined organic extractswere washed with brine, dried over anhydrous MgSO₄, filtered andconcentrated to give a crude oil. Flash chromatography (CH₂Cl₂/MeOH:9/1) gave the title compound as a racemic mixture (2.44 g, 5.62 mmol,42%, yellow oil).

[0270] LC-MS: rt=3.52 min, 434 (M+1, ES+).

[0271] (3,4-Dimethoxy-phenoxy)-acetonitrile

[0272] To a solution of 3,4-dimethoxyphenol (5.0 g, 32.4 mmol) in dryacetone (160 ml), were added chloroacetonitrile (2.05 ml, 32.4 mmol) andanhydrous K₂CO₃ (6.72 g, 48.6 mmol). The reaction mixture was stirred atreflux for 20 h under nitrogen. After cooling, the mixture was filteredand concentrated in vacuo. The residue was combined with H₂O, extractedwith CH₂Cl₂, and the combined organic phases were dried over anhydrousMgSO₄, filtered and concentrated to give a crude oil. Flashchromatography (AcOEt/hexane: 3/7) gave the title product (4.5 g, 68%).

[0273]¹H-NMR (300 MHz, CDCl₃) δ: 6.8 (1H, d), 6.6 (1H, d), 6.5 (1H, dd),4.75 (2H, s), 3.35 (6H, d).

[0274] 2-(3,4-Dimethoxy-phenoxy)-ethylamine

[0275] To a cold (0° C.) suspension of LiAlH₄ (1.73 g, 45.6 mmol) inanhydrous THF (72 ml), was added dropwise a solution of(3,4-dimethoxy-phenoxy)-acetonitrile (5.88 g, 30.4 mmol) in anhydrousTHF (42 ml). The resulting mixture was allowed to warm-up and stirred atRT for 20 h under nitrogen. The reaction mixture was combined with amixture of H₂O/2N NaOH_((aq)) (4/1) to destroy the excess of LiAlH₄. Thewhite suspension was filtered and the solid was washed with CH₂Cl₂. Thecombined organic phases were dried over anhydrous MgSO₄, filtered andconcentrated to give a crude oil. Flash chromatography (CH₂Cl₂/MeOH:9/1) gave the title product (4.65 g, 77%).

[0276]¹H-NMR (300 MHz, CDCl₃) δ: 6.78 (1H, d), 6.55 (1H, d), 6.4 (1H,dd), 3.95 (2H, t), 3.80 (6H, d), 3.05 (2H, t), 1.92 (2H, br.s.).

[0277]N-[2-(3,4-Dimethoxy-phenoxy)-ethyl]-2-(3,4-dimethoxy-phenyl)-acetamide

[0278] To a cold (0° C.) solution of2-(3,4-dimethoxy-phenoxy)-ethylamine (2.3 g, 11.8 mmol) in anhydrous THF(21 ml), were added TEA (1.4 ml, 19.2 mmol) and portionwise3,4-dimethoxyphenylacetylchloride (2.49 g, 11.6 mmol). The resultingmixture was stirred at RT for 20 h under nitrogen. The mixture wascombined with H₂O and extracted three times with CH₂Cl₂. The combinedorganic phases were dried over anhydrous MgSO₄, filtered andconcentrated to give a crude solid. Recrystallisation from diethylethergave the title product (3.59 g, 80%) as a white solid.

[0279]¹H-NMR (300 MHz, CDCl₃) δ: 6.8 (3H, m), 6.4 (1H, d), 6.35 (1H,dd), 5.95 (1H, br.s) 3.95 (2H, t), 3.80 (12H, q), 3.6 (2H, m), 3.55 (2H,s). LC-MS: rt=3.84 min, 376 (M+1, ES+).

[0280] 5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

[0281] To a stirred solution ofN-[2-(3,4-dimethoxy-phenoxy)-ethyl]-2-(3,4-dimethoxy-phenyl)-acetamide(3.6 g, 9.56 mmol) in dry CH₃CN (20 ml), was added POCl₃ (2.62 ml, 28.6mmol). The resulting mixture was stirred at reflux for 3 h undernitrogen. After cooling, the reaction mixture was concentrated in vacuoand the residue was dissolved in MeOH (80 ml). The solution was cooledto 0° C. and NaBH₄ (2.53 g, 67.0 mmol) was added portionwise. Theresulting pale yellow suspension was stirred at RT for 16 h undernitrogen. The reaction mixture was poured into H₂O and extracted threetimes with CH₂Cl₂. The combined organic phases were dried over anhydrousMgSO₄, filtered and concentrated to give a crude oil. Flashchromatography (CH₂Cl₂/MeOH: 9/1) gave the title product (1.14 g, 33%)as a viscous brown oil.

[0282]¹H-NMR (300 MHz, CDCl₃) δ: 6.8-6.6 (5H, m), 6.45 (1H, s), 4.15(1H, m), 3.80 (12H, q), 3.55-2.95 (6H, m). LC-MS: rt=2.99 min, 360 (M+1,ES+).

[0283] (3,4-Dimethoxy-phenylsulfanyl)-acetonitrile

[0284] To a solution of 3,4-dimethoxythiophenol (5.0 g, 29.4 mmol) indry DMF (150 ml), were added chloroacetonitrile (1.85 ml, 29.4 mmol),anhydrous K₂CO₃ (6.09 g, 44.1 mmol) and DMAP (358 mg, 2.9 mmol). Thereaction mixture was stirred at 80° C. for 20 h under nitrogen. Aftercooling, the mixture was filtered and concentrated in vacuo. The residuewas combined with H₂O, extracted with CH₂Cl₂, the combined organicphases were dried over anhydrous MgSO₄, filtered and concentrated togive a crude oil. Flash chromatography (AcOEt) gave the title product(5.16 g, 84%).

[0285]¹H-NMR (300 MHz, CDCl₃) δ: 7.2 (1H, d), 7.15 (1H, d), 6.9 (1H, d),3.85 (6H, d), 3.5 (2H, s).

[0286] 2-(3,4-Dimethoxy-phenylsulfanyl)-ethylamine

[0287] To a cold (0° C.) solution of(3,4-dimethoxy-phenylsulfanyl)-acetonitrile (7.53 g, 36.0 mmol) inanhydrous THF (41 ml), was added portionwise NaBH₄ (1.22 g, 32.0 mmol)and dropwise a solution of BF₃.OEt₂ (5.37 ml, 20.0 mmol) in anhydrousTHF (13.4 ml) over 30 min. The resulting mixture was stirred at RT for 3h under nitrogen. The mixture was concentrated in vacuo, the residue wasdissolved in CH₂Cl₂ and washed with HCl 37%. The aqueous phase wasneutralized with NaOH 30% and extracted with CH₂Cl₂. The combinedorganic phases were dried over anhydrous MgSO₄, filtered andconcentrated to give a crude oil. Flash chromatography (CH₂Cl₂/MeOH:9/1) gave the title product (3.6 g, 46%).

[0288]¹H-NMR (300 MHz, CDCl₃) δ: 7.05 (2H, m), 6.85 (1H, d), 3.80 (6H,d), 2.95 (2H, m), 1.7 (2H, br.s.).

[0289]2-(3,4-Dimethoxy-phenyl)-N-[2-(3,4-dimethoxy-phenylsulfanyl)-ethyl]-acetamide

[0290] To a cold (0° C.) solution of2-(3,4-dimethoxy-phenylsulfanyl)-ethylamine (3.97 g, 18.6 mmol) inanhydrous THF (49 ml), were added TEA (3.11 ml, 18.6 mmol) andportionwise 3,4-dimethoxyphenylacetylchloride (4.0 g, 18.6 mmol). Theresulting mixture was stirred at RT for 20 h under nitrogen. The mixturewas combined with H₂O and extracted three times with CH₂Cl₂. Thecombined organic phases were dried over anhydrous MgSO₄, filtered andconcentrated to give a crude solid. Flash chromatography (AcOEt) gavethe title product (7.08 g, 97%).

[0291]¹H-NMR (300 MHz, CDCl₃) δ: 6.95-6.7 (6H,m), 5.95 (1H,br.s), 3.95(12H,q), 3.5 (2H,s), 3.55 (2H,q), 2.95 (2H,t). LC-MS: rt=3.87 min, 392(M+1, ES+).

[0292]9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene

[0293] To a stirred solution of2-(3,4-dimethoxy-phenyl)-N-[2-(3,4-dimethoxy-phenylsulfanyl)-ethyl]-acetamide(4.0 g, 10.0 mmol) in dry CH₃CN (21 ml), was added POCl₃ (2.80 ml, 30.0mmol). The resulting mixture was stirred at reflux for 3 h undernitrogen. After cooling, the reaction mixture was concentrated in vacuoand the residue was dissolved in MeOH (85 ml). The solution was cooledto 0° C. and NaBH₄ (2.7 g, 69.0 mmol) was added portionwise, theresulting pale yellow suspension was stirred at RT for 16 h undernitrogen. The reaction mixture was poured into H₂O and extracted threetimes with CH₂Cl₂. The combined organic phases were dried over anhydrousMgSO₄, filtered and concentrated to give a crude oil. Flashchromatography (CH₂Cl₂/MeOH: 9/1) gave the title product (1.14 g, 27%)as a viscous brown oil.

[0294]¹H-NMR (300 MHz, CDCl₃) δ: 7.1 (1H, s), 6.8 (4H, s), 4.6 (1H, m),4.15, 3.80 (12H, q), 3.45-2.75 (6H, m). LC-MS: rt=4.39 min, 376 (M+1,ES+).

[0295]9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza-benzocycloheptene-8-carboxylicacid tert-butyl ester

[0296] To a cold (0° C.) stirred solution of9-(3,4-dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9tetrahydro-5-thia-8-aza-benzocycloheptene (417 mg, 1.11 mmol) in dryCH₂Cl₂ (5 ml), were added TEA (168 μL, 1.2 mmol) anddi-tert.-butyl-dicarbonate (262 mg, 1.2 mmol). The resulting mixture wasallowed to warm-up and stirred at RT for 20 h under nitrogen. Thereaction mixture was combined with water, extracted twice with CH₂Cl₂,the combined organic phases were dried over anhydrous MgSO₄, filteredand concentrated to give a crude yellow oil. Flash chromatography(AcOEt) gave the title compound as a pale yellow oil (486 mg, 91%).

[0297]¹H-NMR (300 MHz, CDCl₃) δ: 7.15 (1H, d); 6.6-6.8 (4H, m); 5.05(1H, m); 3.85 (12H, d); 3.65 (2H, m); 3.45 (2H, m); 2.75 (2H, m); 1.45(9H, d).

[0298]9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9-tetrahydro-5λ⁶-thia-8-aza-benzocycloheptene-8-carboxylicacid tert-butyl ester

[0299] To a cold (0° C.) stirred solution of9-(3,4-dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro9H-5-thia-8-aza-benzocycloheptene-8-carboxylic acid tert-butyl ester(100 mg, 0.21 mmol) in dry CH₂Cl₂ (1 ml), was added 3-chloroperbenzoicacid (106 mg, 0.614 mmol). The resulting mixture was stirred at 0° C.for 2 h and allowed to warm-up and stirred at RT overnight. The reactionmixture was combined with water, extracted twice with CH₂Cl₂, thecombined organic phases were dried over anhydrous MgSO₄, filtered andconcentrated to give a crude oil. Flash chromatography (AcOEt/hexane:1/1) gave the title compound as a pale yellow solid (76 mg, 71%).

[0300]¹H-NMR (300 MHz, CDCl₃) δ: 7.15 (1H, d); 6.6-6.8 (4H, m); 5.25(1H, m); 3.85 (12H, d); 3.65 (2H, m); 3.35 (2H, m); 2.75 (2H, m); 1.35(9H, d).

[0301]9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene5,5-dioxide.

[0302] To a stirred solution of9-(3,4-dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9tetrahydro-5λ⁶-thia-8-aza-benzocycloheptene-8-carboxylic acid tert-butylester (310 mg, 0.61 mmol) in dry CH₂Cl₂ (3 ml), was addedtrifluoroacetic acid (372 μL, 4.86 mmol). The resulting mixture wasstirred at RT for 20 h under nitrogen. The reaction mixture was combinedwith water/NaOH 2N, extracted twice with CH₂Cl₂, and the combinedorganic phases were dried over anhydrous MgSO₄, filtered andconcentrated to give a crude oil. Flash chromatography (CH₂Cl₂/MeOH:9/1) gave the title compound as a pale yellow oil (118 mg, 47%).

[0303]¹H-NMR (300 MHz, CDCl₃) δ: 7.6 (1H, d); 6.85 (4H, m); 4.95 (1H,m); 3.95-3.81 (12H, m); 3.45 (4H, m); 3.25 (2H, m).

[0304] 2-(3,4-Dichloro-phenyl)-1-(3,4-dimethoxy-phenyl)-ethanone

[0305] A mixture of (3,4-dichloro-phenyl)-acetic acid (11.14 g, 54.33mmol) and anhydrous DMF (1.45 ml) in thionyl chloride (137 ml) wasstirred at RT, under nitrogen, for 17 h. The excess of thionyl chloridewas removed under vacuum. Anhydrous toluene was added to the residue,which was again concentrated in vacuum (repeated two more times).Powdered anhydrous aluminium chloride (11.57 g, 86.72 mmol) was addedportionwise (exothermic reaction) to a stirred mixture of1,2-dimethoxy-benzene (6.92 ml, 54.34 mmol) and the previous acylchloride in anhydrous dichloromethane (120 ml). An exothermic reactionoccurred and the reaction mixture was heated at reflux for 2 h. Thereaction mixture was allowed to cool to RT and was then poured into amixture of ice (67 g) and aqueous 7.5N HCl (64 ml). The layers wereseparated and the aqueous layer was extracted with dichloromethane. Thecombined organic extracts were washed with brine, dried over magnesiumsulfate, filtered and evaporated to dryness to give a brown residue (oiland solid). After a further drying (HV), anhydrous diethylether wasadded and a beige solid precipitated. The beige solid was filtered andfurther dried (8.33 g, 47%).

[0306] LC-MS: rt=5.25 min, 326 (M+1, ES+).

[0307] 2-(3,4-Dichloro-phenyl)-1-(4,5-dimethoxy-2-nitro-phenyl)-ethanone

[0308] A heterogeneous mixture of2-(3,4-dichloro-phenyl)-1-(3,4-dimethoxy-phenyl)-ethanone (8.33 g, 25.6mmol) in acetic anhydride (65 ml) was added dropwise to a cooled (0° C.)solution of 65% nitric acid (140 ml) and acetic anhydride (21.3 ml). Theresulting mixture was stirred at 0° C. for 2 h. Water was added dropwiseand the resulting heterogeneous mixture was allowed to stir and warm-upslowly. The crude was then filtered and the beige solid was washedseveral times with distilled water and dried under HV (6.98 g, 74%).

[0309] LC-MS: rt=5.43 min, 370 (M+1, ES+).

[0310] 1-(2-Amino4,5-dimethoxy-phenyl)-2-(3,4-dichloro-phenyl)-ethanone

[0311] To a mixture of2-(3,4-dichloro-phenyl)-1-(4,5-dimethoxy-2-nitro-phenyl)-ethanone (9.62g, 25.98 mmol) and palladium on charcoal (2.88 g, 30% in mass) was addeddropwise methanol (500 ml) and the resulting heterogeneous mixture washydrogenated (1 atm) at RT for 4 days. The reaction mixture was filteredover celite, and the celite cake was washed several times with anhydrousmethanol. The filtrate was then evaporated to dryness and the crudebrown oil was purified by flash chromatography(dichloromethane/methanol, 360/1) to give the expected anilinederivative as a brown oil (5.04 g, 57%).

[0312] LC-MS: rt=5.12 min, 341 (M+1, ES+).

[0313]2-Bromo-N-{2-[2-(3,4-dichloro-phenyl)-acetyl]-4,5-dimethoxy-phenyl}-acetamide

[0314] 1-(2-Amino-4,5-dimethoxy-phenyl)-2-(3,4-dichloro-phenyl)-ethanone(5.52 g, 16.24 mmol) was dissolved in dichloromethane (20 ml), distilledwater was then added (2 ml) and the resulting solution was cooled at −5°C. under nitrogen. Bromoacetylbromide (1.63 ml, 18.68 mmol) wasdissolved in dichloromethane (10 ml) and added dropwise to the previoussolution; the temperature was not allowed to exceed +5° C. The reactionmixture was stirred at 0° C. for 15 min and then allowed to reach the RTbefore further stirring for 2.5 h. Dichloromethane was added (30 ml) andthe organic layer was washed with distilled water, saturated NaHCO₃solution, and brine. It was dried over magnesium sulfate, filtered andthe solvent was removed under vacuum. This crude mixture was purified byflash chromatography (dichloromethane/methanol, 360/1) to give theproduct as a yellow solid (5.25 g, 70%).

[0315] LC-MS: rt=5.65 min, 462 (M+1, ES+).

[0316]5-(3,4-Dichloro-benzyl)-7,8-dimethoxy-1,3-dihydro-benzo[e][1,4]diazepin-2-one

[0317]2-Bromo-N-{2-[2-(3,4-dichloro-phenyl)-acetyl]-4,5-dimethoxy-phenyl}-acetamide(5.25 g, 11.39 mmol) was placed at −10° C. under nitrogen. Ammonia inmethanol (7N, 55 ml) was added dropwise at −10° C. and the reactionmixture was heated at 40° C. for 2.5 h, and then at reflux (75° C.) for1 h. The solvent was evaporated under vacuum yielding a yellow solidwhich was dissolved in dichloromethane and washed with water. Theorganic phase was dried over magnesium sulfate, filtered and evaporatedto dryness. Flashchromatography (dichloromethane/methanol, 18/1) yieldedthe expected product as a yellow solid (1.5 g, 35%).

[0318] LC-MS: rt=3.15 min, 380 (M+1, ES+).

[0319]5-(3,4-Dichloro-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one

[0320] A solution of5-(3,4-dichloro-benzyl)-7,8-dimethoxy-1,3-dihydro-benzo[e][1,4]diazepin-2-one(0.48 g, 1.17 mmol) in glacial acetic acid (1.67 ml) and methanol (9.4ml) was stirred at 0° C. under nitrogen. Sodium cyanoborohydride (0.148g, 2.23 mmol) was added portionwise and the reaction mixture was stirredat 0° C. for 30 min, and then at RT for 2 h. Water (17 ml) was addeddropwise and the product was extracted with dichloromethane, washed withaqueous 1N ammonia. The organic phase was dried over magnesium sulfate,filtered and the solvent was removed under vacuum. The resulting yellowoil crystallized under HV (0.19 g, 41%).

[0321] LC-MS: rt=3.55 min, 382 (M+1, ES+).

[0322] B. General Procedure A:

[0323] At −15° C., a solution of the respective amine R₉R₁₀NH (1equivalent) in THF (0.40 M) was added dropwise to a solution of2-bromoacetyl bromide (1 equivalent) in THF (0.20 M). The reactionmixture was then treated dropwise with a solution ofdiisopropylethylamine (4 equivalents) in THF (2.0 M), allowed to warm upslowly to RT (in 30 min) and stirred at RT for 30 min. A solution of therespective benzazepine (1 equivalent) in THF (0.20 M) was added and themixture was stirred at 75° C. for 15 h. After cooling, AcOEt and H₂Owere added, and the aqueous phase was extracted twice with AcOEt. Thecombined organic extracts were washed with brine, dried over anhydrousMgSO₄, filtered and concentrated in vacuo. Flash chromatography yieldedthe expected benzazepine derivative.

EXAMPLE 1

[0324]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-naphthalen-1-ylmethyl-acetamide:

[0325] prepared by reaction of 2-bromoacetyl bromide with1-naphtalenemethylamine and1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.

[0326] LC-MS: rt=3.95 min, 555 (M+1, ES+).

EXAMPLE 2

[0327]N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-acetamide:

[0328] prepared by reaction of 2-bromoacetyl bromide with piperonylamineand1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.

[0329] LC-MS: rt=3.67 min, 549 (M+1, ES+).

EXAMPLE 3

[0330]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-2-yl-acetamide:

[0331] prepared by reaction of 2-bromoacetyl bromide with 2-aminoindanehydrochloride and1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.

[0332] LC-MS: rt=3.83 min, 531 (M+1, ES+).

EXAMPLE 4

[0333]2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-N-indan-2-yl-acetamide:

[0334] prepared by reaction of 2-bromoacetyl bromide with 2-aminoindanehydrochloride and5-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine.

[0335] LC-MS: rt=4.34 min, 533 (M+1, ES+).

EXAMPLE 5

[0336]2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-N-indan-1-yl-acetamide:

[0337] prepared by reaction of 2-bromoacetyl bromide withrac-1-aminoindane and5-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine.

[0338] LC-MS: rt=4.62 min, 533 (M+1, ES+).

EXAMPLE 6

[0339]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide:

[0340] prepared by reaction of 2-bromoacetyl bromide withrac-1-aminoindane and1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.

[0341] LC-MS: rt=3.90 min, 531 (M+1, ES+).

EXAMPLE 7

[0342]2-[9-(3,4-Dimethoxy-benzyl-2,3-dimethoxy-5,5-dioxo-5,6,7,9-tetrahydro-5λ⁶-thia-8-aza-benzocyclohepten-8-yl]-N-indan-2-yl-acetamide:

[0343] prepared by reaction of 2-bromoacetyl bromide with 2-aminoindanehydrochloride and9-(3,4-dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-thia-8-azabenzocycloheptene-5,5-dioxide.

[0344] LC-MS: rt=3.81 min, 581 (M+1, ES+).

EXAMPLE 8

[0345]2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9-tetrahydro-5λ⁶-thia-8-aza-benzocyclohepten-8-yl]-N-indan-1-yl-acetamide:

[0346] prepared by reaction of 2-bromoacetyl bromide withrac-1-aminoindane and9-(3,4-dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene-5,5-dioxide

[0347] LC-MS: rt=4.49 min, 581 (M+1, ES+).

EXAMPLE 9

[0348]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide:

[0349] prepared by reaction of 2-bromoacetyl bromide withS(+)-1-aminoindane and1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.

[0350] LC-MS: rt=3.80 min, 531 (M+1, ES+).

EXAMPLE 10

[0351]2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-N-naphthalen-1-ylmethyl-acetamide:

[0352] prepared by reaction of 2-bromoacetyl bromide with1-naphtalenemethylamine and5-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine.

[0353] LC-MS: rt=4.39 min, 557 (M+1, ES+).

EXAMPLE 11

[0354]2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-N-(2-ethoxy-benzyl)-acetamide:

[0355] prepared by reaction of 2-bromoacetyl bromide with2-ethoxy-benzylamine and5-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine.

[0356] LC-MS: rt=4.34 min, 551 (M+1, ES+).

EXAMPLE 12

[0357]2-[5-(3,4-Dimethoxy-benzyl)7,8-dimethoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-N-indan-1-yl-acetamide:

[0358] prepared by reaction of 2-bromoacetyl bromide withS(+)-1-aminoindane and5-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine.

[0359] LC-MS: rt=4.32 min, 533 (M+1, ES+).

EXAMPLE 13

[0360]2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza-benzocyclohepten-8-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide:

[0361] prepared by reaction of 2-bromoacetyl bromide withrac-1,2,3,4-tetrahydro-naphthalen-1-ylamine and9-(3,4-dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene.

[0362] LC-MS: rt=5.01 min, 563 (M+1, ES+).

EXAMPLE 14

[0363]N-Benzyl-2-[5-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetamide:

[0364] prepared by reaction of 2-bromoacetyl bromide with benzylamineand5-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine.

[0365] LC-MS: rt=4.05 min, 507 (M+1, ES+).

EXAMPLE 15

[0366]2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza-benzocyclohepten-8-yl]-N-indan-1-yl-acetamide:

[0367] prepared by reaction of 2-bromoacetyl bromide withS(+)-1-aminoindane and9-(3,4-dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene.

[0368] LC-MS: rt=4.85 min, 549 (M+1, ES+).

EXAMPLE 16

[0369]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(4-methoxy-indan-1-yl)-acetamide:

[0370] prepared by reaction of 2-bromoacetyl bromide withrac-4-methoxy-indan-1-ylamine and1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.

[0371] LC-MS: rt=3.83 min, 561 (M+1, ES+).

EXAMPLE 17

[0372]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-phenyl-indan-1-yl)-acetamide:

[0373] prepared by reaction of 2-bromoacetyl bromide withrac-3-phenyl-indan-1-ylamine and1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.

[0374] LC-MS: rt=4.42 min, 607 (M+1, ES+).

EXAMPLE 18

[0375]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(4-methyl-indan-1-yl)-acetamide:

[0376] prepared by reaction of 2-bromoacetyl bromide withrac-4-methyl-indan-1-ylamine and1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.

[0377] LC-MS: rt 4.02 min, 545(M+1, ES+).

EXAMPLE 19

[0378]2-[8-Benzyloxy-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide:

[0379] prepared by reaction of 2-bromoacetyl bromide withS(+)-1-aminoindane and1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.

[0380] LC-MS: rt=4.39 min, 607 (M+1, ES+).

[0381] C. General Procedure B:

[0382] To a solution of the respective[1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid (1equivalent) in anhydrous DMF (0.04 M) was added successively PyBOP (1.1equivalents), the respective amine (1 equivalent) andN,N-diisopropylethylamine (2.3 equivalents). The resulting mixture wasstirred at RT for 15 h under nitrogen. Upon completion of the reaction,AcOEt was added, and the organic phase was washed with brine, dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Flashchromatography provided the corresponding benzazepine derivative.

EXAMPLE 20

[0383]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-2-yl-2-phenyl-acetamide:

[0384] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 2-aminoindane hydrochloride.

[0385] LC-MS: rt=4.26 min, 607 (M+1, ES+).

EXAMPLE 21

[0386]N-Butyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide:

[0387] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with n-butylamine.

[0388] LC-MS: rt=3.91 min, 547 (M+1, ES+).

EXAMPLE 22

[0389]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-2-phenyl-acetamide:

[0390] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with S(+)-1-aminoindane.

[0391] LC-MS: rt=4.09 min and rt=4.39 min (diastereoisomers), 607 (M+1,ES+).

EXAMPLE 23

[0392]N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide:

[0393] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with piperonylamine.

[0394] LC-MS: rt=3.88 min and rt=3.98 min (diastereoisomers), 625 (M+1,ES+).

EXAMPLE 24

[0395]N-Cyclopentyl-2-[1-(3,4dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide:

[0396] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with cyclopentylamine.

[0397] LC-MS: rt=3.79 min and rt=3.92 min (diastereoisomers), 559 (M+1,ES+).

EXAMPLE 25

[0398]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-furan-2-ylmethyl-2-phenyl-acetamide:

[0399] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with furfurylamine.

[0400] LC-MS: rt=3.72 min and rt=3.85 min (diastereoisomers), 571 (M+1,ES+).

EXAMPLE 26

[0401]{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-aceticacid ethyl ester:

[0402] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with glycine ethyl ester hydrochloride.

[0403] LC-MS: rt=3.72 min, 577 (M+1, ES+).

EXAMPLE 27

[0404]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-pyridin-4-ylmethyl-acetamide:

[0405] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 4-picolylamine.

[0406] LC-MS: rt=3.09 min, 582 (M+1, ES+).

EXAMPLE 28

[0407]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-pyridin-3-ylmethyl-acetamide:

[0408] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 3-picolylamine.

[0409] LC-MS: rt=3.20 min, 582 (M+1, ES+).

EXAMPLE 29

[0410]N-Cyclopropyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide:

[0411] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with cyclopropylamine.

[0412] LC-MS: rt=3.59 min, 531 (M+1, ES+).

EXAMPLE 30

[0413]2-[1-(3,4-Dimethoxy-benzyl)-7.8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-oxo-tetrahydro-furan-3-yl)-2-phenyl-acetamide:

[0414] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 2-amino-4-butyrolactone hydrobromide.

[0415] LC-MS: rt=3.46 min, 575 (M+1, ES+).

EXAMPLE 31

[0416]2-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-3-hydroxy-propionicacid methyl ester:

[0417] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with L-serine methyl ester hydrochloride.

[0418] LC-MS: rt=3.40 min, 593 (M+1, ES+).

EXAMPLE 32

[0419]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-ethylcarbamoylmethyl-2-phenyl-acetamide:

[0420] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 2-amino-N-ethyl-acetamide.

[0421] LC-MS: rt=3.37 min, 576 (M+1, ES+).

EXAMPLE 33

[0422]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-[(ethyl-methyl-carbamoyl)-methyl]-2-phenyl-acetamide:

[0423] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 2-amino-N-ethyl-N-methyl-acetamide.

[0424] LC-MS: rt=3.42 min, 590 (M+1, ES+).

EXAMPLE 34

[0425]3-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-propionicacid methyl ester:

[0426] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 3-amino-propionic acid methyl ester.

[0427] LC-MS: rt=3.52 min, 577 (M+1, ES+).

EXAMPLE 35

[0428]N-(1H-Benzoimidazol-2-ylmethyl)-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide:

[0429] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 2-aminomethyl-benzimidazole dihydrochloride hydrate.

[0430] LC-MS: rt=3.36 min, 621 (M+1, ES+).

EXAMPLE 36

[0431]3-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-N,N-dimethyl-propionamide:

[0432] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 3-amino-N,N-dimethyl-propionamide.

[0433] LC-MS: rt=3.42 min, 590 (M+1, ES+).

EXAMPLE 37

[0434]3-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-N-ethyl-N-methyl-propionamide:

[0435] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 3-amino-N-ethyl-N-methyl-propionamide.

[0436] LC-MS: rt=3.40 min, 604 (M+1, ES+).

EXAMPLE 38

[0437]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-methyl-1H-indol-3-ylmethyl)-2-phenyl-acetamide:

[0438] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with C-(1-methyl-1H-indol-3-yl)-methylamine.

[0439] LC-MS: rt=3.99 min and rt=4.12 min (diastereoisomers), 634 (M+1,ES+).

EXAMPLE 39

[0440]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-isoxazol-5-ylmethyl-2-phenyl-acetamide:

[0441] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with C-isoxazol-5-yl-methylamine hydrochloride.

[0442] LC-MS: rt=3.65 min, 572 (M+1, ES+).

EXAMPLE 40

[0443]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1H-indol-3-ylmethyl)-2-phenyl-acetamide:

[0444] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with C-(1H-indol-3-yl)-methylamine dihydrochloride.

[0445] LC-MS: rt=3.82 mm and rt=3.96 min (diastereoisomers), 620 (M+1,ES+).

EXAMPLE 41

[0446]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-methyl-1H-benzoimidazol-2-ylmethyl)-2-phenyl-acetamide:

[0447] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with C-(1-methyl-1H-benzoimidazol-2-yl)-methylamine.

[0448] LC-MS: rt=3.50 min, 635 (M+1, ES+).

EXAMPLE 42

[0449]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-isoquinolin-1-ylmethyl-2-phenyl-acetamide:

[0450] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with C-isoquinolin-1-yl-methylamine dihydrochloride.

[0451] LC-MS: rt=3.88 min, 632 (M+1, ES+).

EXAMPLE 43

[0452]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-(4-[1,2,3]thiadiazol-4-yl-benzyl)-acetamide:

[0453] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 4-(1,2,3-thiadiazol-4-yl)benzylamine hydrochloride.

[0454] LC-MS: rt=4.09 min, 665 (M+1, ES+).

EXAMPLE 44

[0455]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-methyl-1H-indazol-3-ylmethyl)-2-phenyl-acetamide:

[0456] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with C-(1-methyl-1H-indazol-3-yl)-methylamine hydrochloride.

[0457] LC-MS: rt=3.83 min, 635 (M+1, ES+).

EXAMPLE 45

[0458]N-Cyanomethyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide:

[0459] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with amino acetonitrile hydrochloride.

[0460] LC-MS: rt=3.42 min and rt=3.58 min (diastereoisomers), 530 (M+1,ES+).

EXAMPLE 46

[0461]N-(2-Acetylamino-ethyl)-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide:

[0462] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with N-acetylethylendiamine.

[0463] LC-MS: rt=3.13 min, 576 (M+1, ES+).

EXAMPLE 47

[0464]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-(2,2,2-trifluoro-ethyl)-acetamide:

[0465] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 2,2,2-trifluoroethylamine.

[0466] LC-MS: rt=4.11 min, 573 (M+1, ES+).

EXAMPLE 48

[0467]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-methylsulfanyl-ethyl)-2-phenyl-acetamide:

[0468] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 2-(methylthio)-ethylamine.

[0469] LC-MS: rt=3.63 min, 565 (M+1, ES+).

EXAMPLE 49

[0470]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-quinolin-2-ylmethyl-acetamide:

[0471] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with C-quinolin-2-yl-methylamine dihydrochloride.

[0472] LC-MS: rt=3.91 min, 632 (M+1, ES+).

EXAMPLE 50

[0473]N-(2-Cyano-ethyl)-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide:

[0474] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 3-aminopropionitrile.

[0475] LC-MS: rt=3.30 min, 544 (M+1, ES+).

EXAMPLE 51

[0476]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-methoxy-propyl)-2-phenyl-acetamide:

[0477] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 3-methoxypropylamine.

[0478] LC-MS: rt=3.32 min, 563 (M+1, ES+).

EXAMPLE 52

[0479]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-ethoxy-propyl)-2-phenyl-acetamide:

[0480] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 3-ethoxypropylamine.

[0481] LC-MS: rt=3.51 min, 577 (M+1, ES+).

EXAMPLE 53

[0482]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide:

[0483] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with ammonium chloride.

[0484] LC-MS: rt=3.15 min, 491 (M+1, ES+).

EXAMPLE 54

[0485]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-pyrazin-2-ylmethyl-acetamide:

[0486] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with C-pyrazin-2-yl-methylamine hydrochloride.

[0487] LC-MS: rt=3.33 min, 583 (M+1, ES+).

EXAMPLE 55

[0488]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-prop-2-ynyl-acetamide:

[0489] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with propargylamine.

[0490] LC-MS: rt=3.36 min and rt=3.51 min (diastereoisomers), 529 (M+1,ES+).

EXAMPLE 56

[0491]N-tert-Butyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide:

[0492] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with tert-butylamine.

[0493] LC-MS: rt=3.69 min, 547 (M+1, ES+).

EXAMPLE 57

[0494]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-methyl-butyl)-2-phenyl-acetamide:

[0495] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 1-amino-3-methylbutane.

[0496] LC-MS: rt=3.89 min, 561 (M+1, ES+).

EXAMPLE 58

[0497]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3,3-dimethyl-butyl)-2-phenyl-acetamide:

[0498] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 3,3-dimethylbutylamine.

[0499] LC-MS: rt=4.20 min, 575 (M+1, ES+).

EXAMPLE 59

[0500]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-ethyl-propyl)-2-phenyl-acetamide:

[0501] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 1-ethylpropylamine.

[0502] LC-MS: rt=3.77 min, 561 (M+1, ES+).

EXAMPLE 60

[0503]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-ethylsulfanyl-ethyl)-2-phenyl-acetamide:

[0504] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 2-(ethylthio)ethylamine hydrochloride.

[0505] LC-MS: rt=3.72 min, 579 (M+1, ES+).

EXAMPLE 61

[0506]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-hydroxy-ethyl)-2-phenyl-acetamide:

[0507] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with ethanolamine.

[0508] LC-MS: rt=3.19 min, 535 (M+1, ES+).

EXAMPLE 62

[0509]2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-hydroxy-propyl)-2-phenyl-acetamide:

[0510] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with 3-amino-1-propanol.

[0511] LC-MS: rt=3.13 min, 549 (M+1, ES+).

EXAMPLE 63

[0512][1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid N′,N′-dimethyl-hydrazide:

[0513] prepared by reaction of[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid with N,N-dimethylhydrazine.

[0514] LC-MS: rt=3.20 min, 534 (M+1, ES+).

[0515] D. Variation of Substituents on Position 8:

[0516] General Procedure:

[0517] To a solution of the respective8-benzyloxy-1,3,4,5-tetrahydro-benzazepine in methanol (0.07 M) wasadded palladium (10 wt. % on activated charcoal; 10% of the benzyletherweight) and the resulting heterogeneous mixture was vigorously stirredunder an hydrogen atmosphere at RT until disappearance of benzylether(TLC). Upon complete conversion the mixture was filtered through celiteand concentrated in vacuo. Flash chromatography yielded the pure phenolderivative. To a solution of this phenol derivative (1 equivalent) inanhydrous DMF (0.04 M) was added successively anhydrous potassiumcarbonate (5 equivalents) and the respective electrophile (1.2equivalents). The resulting heterogeneous mixture was stirred at 50° C.for up to 15 h. After reaction the mixture was dissolved in AcOEt andwashed with a saturated aqueous solution of NaHCO₃. The organic phasewas dried over anhydrous MgSO₄, filtered and concentrated in vacuo.Flash chromatography provided the pure benzazepine derivative.

EXAMPLE 64

[0518]2-[1-(3,4-Dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide:

[0519] prepared by hydrogenolysis of2-[8-benzyloxy-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide.

[0520] LC-MS: rt=3.64 min, 517 (M+1, ES+).

EXAMPLE 65

[0521]N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide:

[0522] prepared by hydrogenolysis ofN-benzo[1,3]dioxol-5-ylmethyl-2-[8-benzyloxy-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide.

[0523] LC-MS: rt=3.77 min, 611 (M+1, ES+).

EXAMPLE 66

[0524]2-[8-Allyloxy-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide:

[0525] prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamidewith allylbromide.

[0526] LC-MS: rt=4.05 min, 557 (M+1, ES+).

EXAMPLE 67

[0527]2-[1-(3,4-Dimethoxy-benzyl)-7-methoxy-8-propoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide:

[0528] prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamidewith 1-bromopropane.

[0529] LC-MS: rt=4.13 min, 559 (M+1, ES+).

EXAMPLE 68

[0530]2-[1-(3,4-Dimethoxy-benzyl)-8-isopropoxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide:

[0531] prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamidewith 2-bromopropane.

[0532] LC-MS: rt=4.07 min, 559 (M+1, ES+).

EXAMPLE 69

[0533]2-[8-(2,2-Difluoro-ethoxy)-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide:

[0534] prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamidewith 2-bromo-1,1-difluoroethane.

[0535] LC-MS: rt=4.14 min, 581 (M+1, ES+).

EXAMPLE 70

[0536]N-Benzo[1,3]dioxol-5-ylmethyl-2-[8-(2,2-difluoro-ethoxy)-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide:

[0537] prepared by reaction ofN-benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamidewith 2-bromo-1,1-difluoroethane.

[0538] LC-MS: rt=4.20 min and rt=4.37 min (diastereoisomers), 675 (M+1,ES+).

EXAMPLE 71

[0539]N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-8-isopropoxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide:

[0540] prepared by reaction ofN-benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamidewith 2-bromopropane.

[0541] LC-MS: rt=3.96 min, 653 (M+1, ES+).

[0542] E. 1,4-Benzodiazepin-2-ones:

EXAMPLE 72

[0543] 2-[5-(3,4-Dichloro-benzyl)-7,8-dimethoxy-2-oxo-1,2,3,5-tetrahydrobenzo[e][1,4]diazepin-4-yl]-N-indan-1-yl-acetamide:

[0544] prepared according to general procedure A, by reaction of2-bromoacetyl bromide with S(+)-1-aminoindane and5-(3,4-dichloro-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one.

[0545] LC-MS: rt=5.18 min, 554.47 (M+1, ES+).

[0546] F. Optically Pure Benzazepines:

[0547] The preparation of enantiomerically pure1-substituted-2-tetrahydrobenzazepine derivatives was based on themethodology described by Polniaszek, in the case of optically pure1-substituted tetrahydroisoquinolines (Polniaszek R. P. et al., J. Am.Chem. Soc. 1989, 111, 4859-4863). For the Bischler-Napieralski reaction,the experimental conditions described by Kano were employed (S. Kano etal., Chem. Pharm. Bull. 1977, 25, 10, 2510-2515).

[0548] 1-(S)-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1Hbenzo[c]azepine.

[0549]2-(3,4-Dimethoxy-phenyl)-N-[3-(3,4-dimethoxy-phenyl)-propyl]-N-(1-(S)-phenyl-ethyl)-acetamidewas prepared according to the described procedures (Polniaszek R. P. etal., J. Am. Chem. Soc. 1989, 111, 4859-4863).

[0550] A mixture of2-(3,4-dimethoxy-phenyl)-N-[3-(3,4-dimethoxy-phenyl)-propyl]-N-(1-(S)-phenyl-ethyl)-acetamide(7.0 g, 14.65 mmol) and phosphorus oxide chloride (13.4 ml, 146.5 mmol)in anhydrous acetonitrile, (160 ml) was heated at reflux for 6.5 h,under nitrogen. After cooling to RT, the volatiles were removed undervacuum and the resulting oil was dissolved in anhydrous methanol beforeevaporation to dryness (repeated twice). The resulting brown oil wasdissolved again in anhydrous methanol (122 ml) and cooled at −78° C.,under nitrogen. Then, sodium borohydride (3.02 g, 79.99 mmol) was addedportionwise in 5 h to the reaction mixture kept at −78° C. The reactionwas quenched by dropwise addition of aqueous 1N HCl (8 ml) and themixture was allowed to warm to RT before the solvent was removed undervacuum and water (175 ml) was added. After extraction with CH₂Cl₂ (4×150ml), the organic layer was dried over anhydrous magnesium sulfate andthe solvent was removed under vacuum. The resulting crude oil waspurified by flash chromatography (CH₂Cl₂/CH₃OH: 36/1) giving the purediastereoisomer1-(S)-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2-(1-(S)-phenyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepineas a yellow oil (1.36 g, 20%). This compound (225 mg, 0.49 mmol) wasthen dissolved in methanol (8 ml) and 10% palladium on charcoal (225 mg)and trifluoroacetic acid (0.05 ml, 0.65 mmol) were added. The resultingmixture was stirred under hydrogen (1 atm), at RT for 13 h. Afterfiltration over celite and evaporation to dryness, water (10 ml) andaqueous 2N NaOH (0.35 ml, 0.70 mmol) were added. The mixture wasextracted with CH₂Cl₂ (3×15 ml) and the organic extract was dried overanhydrous MgSO₄, filtered and concentrated under vacuum. The opticallypure1-(S)-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepinewas obtained as a yellow oil (152 mg, 88%).

[0551] LC-MS: rt=3.04 min, 358 (M+1, ES+).

EXAMPLE 73

[0552]2-[1-(S)-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-(S)-1-yl-acetamide:

[0553] prepared according to general procedure A, by reaction of2-bromoacetyl bromide with S(+)-1-aminoindane and1-(S)-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.

[0554] LC-MS: rt=3.76 min, 531 (M+1, ES+).

EXAMPLE 74

[0555]2-[1-(S)-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-2-yl-acetamide:

[0556] prepared according to general procedure A, by reaction of2-bromoacetyl bromide with 2-aminoindane hydrochloride and1-(S)-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.

[0557] LC-MS: rt=3.70 min, 531 (M+1, ES+).

1. Compounds of the general formula (I)

wherein: R¹, R², R³, R⁴ independently represent cyano, nitro, halogen,hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, loweralkenyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyloxy, aryloxy,aralkyloxy, heterocyclyloxy, heterocyclylalkyloxy, R¹¹CO—, NR¹²R¹³CO—,R¹²R¹³N—, R¹¹OOC—, R¹¹SO₂NH—, or R¹⁴—CO—NH—, or R² and R³ together aswell as R¹ and R² together and R³ and R⁴ together may form with thephenyl ring a five, six or seven-membered saturated ring containing oneor two oxygen atoms; R⁵ represents aryl, aralkyl, lower alkyl, loweralkenyl, trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyl-loweralkyl; R⁶ represents hydrogen, aryl, aralkyl, lower alkyl, loweralkenyl, trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyl-loweralkyl; R⁷, R⁸ independently represent hydrogen, aryl, aralkyl, loweralkyl, lower alkenyl, cycloalkyl, heterocyclyl or heterocyclyl-loweralkyl; R⁹, R¹⁰ independently represent hydrogen, aryl, arylcycloalkyl,aralkyl, lower alkyl, lower alkenyl, lower alkinyl, cycloalkyl,heterocyclyl or heterocyclyl-lower alkyl, in which one, several, or allhydrogen atoms may be replaced by halogen or in which one or twohydrogen atoms may be replaced by hydroxy, nitro, cyano,trifluoromethyl, trifluoromethoxy, —O-lower alkyl, —NH-lower alkyl,—N(lower alkyl)₂, —S-lower alkyl, —COO-lower alkyl, —CONH-lower alkyl,—CON(lower alkyl)₂, —CO-lower alkyl, —NHCO-lower alkyl, —O-lower alkenylwith 3 to 5 carbon atoms, —NH-lower alkenyl with 3 to 5 carbon atoms,—N(lower alkenyl with 3 to 5 carbon atoms)₂, —S lower alkenyl with 3 to5 carbon atoms, —COO-lower alkenyl with 3 to 5 carbon atoms, —CONH-loweralkenyl with 3 to 5 carbon atoms, —CON(lower alkenyl with 3 to 5 carbonatoms)₂, —CO-lower alkenyl with 3 to 5 carbon atoms, —NHCO-lower alkenylwith 3 to 5 carbon atoms, —O-lower alkinyl with 3 to 5 carbon atoms,—NH-lower alkinyl with 3 to 5 carbon atoms, —N(lower alkinyl with 3 to 5carbon atoms)₂, —S-lower alkinyl with 3 to 5 carbon atoms, —COO-loweralkinyl with 3 to 5 carbon atoms, —CONH-lower alkinyl with 3 to 5 carbonatoms, CON(lower alkinyl with 3 to 5 carbon atoms)₂, —CO-lower alkinylwith 3 to 5 carbon atoms, —NHCO-lower alkinyl with 3 to 5 carbon atoms;R¹¹ represents lower alkyl, aryl, aralkyl, heterocyclyl orheterocyclyl-lower alkyl; R¹² and R¹³ independently represent hydrogen,lower alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl orheterocyclyl-lower alkyl; R¹⁴ represents lower alkyl, aryl, cycloalkyl,heterocyclyl, R¹²R¹³N—, R¹¹O—; —X—Y— independently represents —CH₂—CH₂—,—O—CH₂—, —S—CH₂—, —SO₂—CH₂— and —NR¹⁵—CO—; R¹⁵ represents hydrogen,lower alkyl or aralkyl; and optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates, mixtures of diastereoisomeric racemates, or meso forms andpharmaceutically acceptable salts thereof.
 2. Compounds of the formula(II)

wherein: R¹, R², R³, R⁴ independently represent cyano, nitro, halogen,hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, loweralkenyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyloxy, aryloxy,aralkyloxy, heterocyclyloxy, heterocyclylalkyloxy, R¹¹CO—, NR¹²R¹³CO—,R¹²R¹³N—, R¹¹OOC—, R¹¹SO₂NH—, or R¹⁴—CO—NH—, or R² and R³ together aswell as R¹ and R² together and R³ and R⁴ together may form with thephenyl ring a five, six or seven-membered saturated ring containing oneor two oxygen atoms; R⁵ independently represents aryl, aralkyl, loweralkyl, lower alkenyl, trifluoromethyl, cycloalkyl, heterocyclyl orheterocyclyl-lower alkyl; R⁶ independently represents hydrogen, aryl,aralkyl, lower alkyl, lower alkenyl, trifluoromethyl, cycloalkyl,heterocyclyl or heterocyclyl-lower alkyl; R⁷, R⁸, R⁹, R¹⁰ independentlyrepresent hydrogen, aryl, aralkyl, lower alkyl, lower alkenyl,cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl; R¹¹ representslower alkyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl;R¹² and R¹³ independently represent hydrogen, lower alkyl, cycloalkyl,aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl; R¹⁴ representslower alkyl, aryl, cycloalkyl, heterocyclyl, R¹²R¹³N—, R¹¹O—; —X—Y—independently represents —CH₂—CH₂—, —O—CH₂—, —S—CH₂—, —SO₂—CH₂— and—NR¹⁵—CO—; R¹⁵ represents hydrogen, lower alkyl or aralkyl; andoptically pure enantiomers, mixtures of enantiomers such as, forexample, racemates, optically pure diastereoisomers, mixtures ofdiastereoisomers, diastereoisomeric racemates, mixtures ofdiastereoisomeric racemates, or meso forms and pharmaceuticallyacceptable salts thereof.
 3. Compounds of the formula (III)

wherein: R′¹ and R′² independently represent hydrogen, hydroxy, loweralkoxy, lower alkenyloxy or halogen or may form with the phenyl ring afive, six or seven membered-ring containing one or two oxygen atoms; R′³represents aryl, aralkyl, lower alkyl, lower alkenyl, cycloalkyl,heterocyclyl or heterocyclyl-lower alkyl; R′⁴, R′⁵ independentlyrepresent hydrogen, aryl, aralkyl, lower alkyl, lower alkenyl,cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl; —X—Y—independently represents —CH₂—CH₂—, —O—CH₂—, —S—CH₂—, —SO₂—CH₂— and—NR′⁶—CO—; R′⁶ represents hydrogen, lower alkyl or aralkyl; andoptically pure enantiomers, mixtures of enantiomers such as, forexample, racemates, optically pure diastereoisomers, mixtures ofdiastereoisomers, diastereoisomeric racemates, mixture ofdiastereoisomeric racemates, or meso forms and pharmaceuticallyacceptable salts thereof.
 4. A compound according to any of claims 1 to3, selected from the group consisting of2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-naphthalen-1-ylmethyl-acetamide;N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-2-yl-acetamide;2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-N-indan-2-yl-acetamide;2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-N-indan-1-yl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide;2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9-tetrahydro-5λ-thia-8-aza-benzocyclohepten-8-yl]-N-indan-2-yl-acetamide;2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9-tetrahydro-5λ-thia-8-aza-benzocyclohepten-8-yl]-N-indan-1-yl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-2-yl-2-phenyl-acetamide;2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza-benzocyclohepten-8-yl]-N-naphthalen-1-ylmethyl-acetamide;2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza-benzocyclohepten-8-yl]-N-(2-ethoxy-benzyl)-acetamide;2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza-benzocyclohepten-8-yl]-N-indan-1-yl-acetamide;2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide;N-Benzyl-2-[9-(3,4-dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza-benzocyclohepten-8-yl]-acetamide;2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-N-indan-1-yl-acetamide;N-Butyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-2-phenyl-acetamide;N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;N-Cyclopentyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-furan-2-ylmethyl-2-phenyl-acetamide;{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-aceticacid ethyl ester;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-pyridin-4-ylmethyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-pyridin-3-ylmethyl-acetamide;N-Cyclopropyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-oxo-tetrahydro-furan-3-yl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(4-methoxy-indan-1-yl)-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-phenyl-indan-1-yl)-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(4-methyl-indan-1-yl)-acetamide;2-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-3-hydroxy-propionicacid methyl ester;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-ethylcarbamoylmethyl-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-[(ethyl-methyl-carbamoyl)-methyl]-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide;2-[8-Benzyloxy-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide;3-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-propionicacid methyl ester;N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;N-(1H-Benzoimidazol-2-ylmethyl)-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;3-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-N,N-dimethyl-propionamide;3-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-N-ethyl-N-methyl-propionamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-methyl-1H-indol-3-ylmethyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-isoxazol-5-ylmethyl-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1H-indol-3-ylmethyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-methyl-1H-benzoimidazol-2-ylmethyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-isoquinolin-1-ylmethyl-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-(4-[1,2,3]thiadiazol-4-yl-benzyl)-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-methyl-1H-indazol-3-ylmethyl)-2-phenyl-acetamide;N-Cyanomethyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;N-(2-Acetylamino-ethyl)-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-(2,2,2-trifluoro-ethyl)-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-methylsulfanyl-ethyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-quinolin-2-ylmethyl-acetamide;N-(2-Cyano-ethyl)-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-methoxy-propyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-ethoxy-propyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-pyrazin-2-ylmethyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-prop-2-ynyl-acetamide;N-tert-Butyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-methyl-butyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3,3-dimethyl-butyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-ethyl-propyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-ethylsulfanyl-ethyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-hydroxy-ethyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-hydroxy-propyl)-2-phenyl-acetamide;[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-aceticacid N′,N′-dimethyl-hydrazide;2-[8-Allyloxy-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7-methoxy-8-propoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-8-isopropoxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide;2-[8-(2,2-Difluoro-ethoxy)-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide;N-Benzo[1,3]dioxol-5-ylmethyl-2-[8-(2,2-difluoro-ethoxy)-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-8-isopropoxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;2-[5-(3,4-Dichloro-benzyl)-7,8-dimethoxy-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-N-indan-1-yl-acetamide;2-[1-(S)-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide;2-[1-(S)-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-2-yl-acetamide5. A compound according to any of claims 1 to 4, selected from the groupconsisting of2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-2-yl-acetamide;2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-N-indan-1-yl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-2-yl-2-phenyl-acetamide;N-Butyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-2-phenyl-acetamide;N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;N-Cyclopentyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-furan-2-ylmethyl-2-phenyl-acetamide;{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-aceticacid ethyl ester;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-pyridin-3-ylmethyl-acetamide;3-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetylamino}-propionicacid methyl ester;N-(1H-Benzoimidazol-2-ylmethyl)-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-methyl-1H-indol-3-ylmethyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-isoxazol-5-ylmethyl-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1H-indol-3-ylmethyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-isoquinolin-1-ylmethyl-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-(4-[1,2,3]thiadiazol-4-yl-benzyl)-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-methyl-1H-indazol-3-ylmethyl)-2-phenyl-acetamide;N-Cyanomethyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-(2,2,2-trifluoro-ethyl)-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-methylsulfanyl-ethyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-quinolin-2-ylmethyl-acetamide;N-(2-Cyano-ethyl)-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-methoxy-propyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-ethoxy-propyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-pyrazin-2-ylmethyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-N-prop-2-ynyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-methyl-butyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3,3-dimethyl-butyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(1-ethyl-propyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-ethylsulfanyl-ethyl)-2-phenyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2-hydroxy-ethyl)-2-phenyl-acetamide;2-[8-Allyloxy-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-7-methoxy-8-propoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-8-isopropoxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide;2-[8-(2,2-Difluoro-ethoxy)-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide;N-Benzo[1,3]dioxol-5-ylmethyl-2-[8-(2,2-difluoro-ethoxy)-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-8-isopropoxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide;2-[1-(S)-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide;2-[1-(S)-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-2-yl-acetamide;6. Pharmaceutical compositions for the treatment of disorders which areassociated with the role of orexin, especially disorders such as obesityand sleep disorders, containing one or more compounds of any one ofclaims 1 to 5, or a pharmaceutically acceptable salt thereof, and usualcarrier materials and adjuvants.
 7. The compounds of any one of claims 1to 5, or a pharmaceutically acceptable salt thereof, for use asmedicaments for the treatment of disorders which are associated with arole of orexin, especially obesity and sleep disorders.
 8. A method oftreating or preventing diseases or disorders where an antagonist of ahuman orexin receptor is required, which comprises administering to asubject in need thereof an effective amount of a compound as claimed inany one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.9. A process for the manufacture of pharmaceutical compositions for thetreatment of disorders associated with the role of orexin, especiallyobesity and sleep disorders, containing one or more compounds as claimedin any one of claims 1 to 5, or a pharmaceutically acceptable salt orsalts thereof, as active ingredients which process comprises mixing oneor more active ingredient or ingredients with pharmaceuticallyacceptable excipients and adjuvants in a manner known per se.
 10. Thenovel compounds, processes and methods as well as the use of suchcompounds substantially as described herein before.